Derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones, their preparation processes and their use as medicaments

ABSTRACT

A method of treating a disorder selected from the group consisting of acromegaly, hypophyseal adenomas, endocrine gastroenteropancreatic tumors including carcinoid syndrome and gastrointestinal bleeding in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula 
                         
in racemic or enantiomeric form.

This application is a division of U.S. patent application Ser. No. 10/813,139 filed Mar. 30,2004, now U.S. Pat. No. 7,199,145 which is a division of U.S. patent application Ser. No. 10/048,144 filed Jan. 23, 2002, now U.S. Pat. No. 6,759,415 which is a 371 of PCT/FR00/02164 filed Jul. 28, 2000.

The invention relates to new derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones of general formula (I) represented below, their preparation processes and their use as medicaments. These compounds have a good affinity with certain sub-types of somatostatin receptors and therefore have useful pharmacological properties. The invention also relates to the pharmaceutical compositions containing said compounds and their use for the preparation of a medicament intended to treat pathological states or diseases in which one (or more) somatostatin receptors are involved.

Somatostatin (SST) is a cyclic tetradecapeptide which was isolated for the first time from the hypothalamus as a substance which inhibits the growth hormone (Brazeau P. et al., Science 1973, 179, 77-79). It also operates as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995, 16, 427-442). Molecular cloning has allowed it to be shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.

The heterogeneity of the biological functions of somatostatin has led to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (Yamada et al., Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhoea syndrome, diarrhoea associated with AIDS, diarrhoea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumours; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.

Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., The European Journal of Medicine, 1993, 2, 97-105), there can be mentioned for example: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumours, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, as well as Alzheimer's disease. Osteoporosis can also be mentioned.

The Applicant found that the compounds of general formula (I) described hereafter have an affinity and a selectivity for the somatostatin receptors. As somatostatin and its peptide analogues. often have a poor bioavailability by oral route and a low selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110), said compounds, non-peptide agonists or antagonists of somatostatin, can be advantageously used to treat pathological states or illnesses as presented above and in which one (or more) somatostatin receptors are involved. Preferably, said compounds can be used for the treatment of acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumours including carcinoid syndrome.

The compounds of the present invention correspond to general formula (I)

in racemic, enantiomeric form or all combinations of these forms, in which:

-   R1 represents a (C₁-C₁₂)alkyl, (C₀-C₆)alkyl-C(O)—O-Z1,     (C₀-C₆)alkyl-C(O)—NH—(CH₂)_(p)-Z2 or aryl radical optionally     substituted, -   Z1 represents H, a (C₁-C₆) alkyl, —(CH₂)_(p)-aryl radical; -   Z2 represents an amino, (C₁-C₁₂)alkylamino, (C₃-C₈)cycloalkylamino,     N,N-di-(C₁-C₁₂)alkylamino, NH—C(O)—O—(CH₂)_(p)-phenyl,     NH—C(O)—O—(CH₂)_(p)—(C₁-C₆)alkyl radical, an optionally substituted     carbocyclic or heterocyclic aryl radical or an optionally     substituted heterocyclic non aromatic radical; -   R2 represents H, (C₁-C₁₂)alkyl or aryl optionally substituted; -   R3 represents H or (CH₂)_(p)-Z3; -   Z3 represents (C₁-C₁₂)alkyl, (C₁-C₁₂)alkenyl, (C₃-C₈)cycloalkyl,     —Y1—(CH₂)_(p)-phenyl-(X1)_(n), —S—(C₁-C₁₂)alkyl,     S—(C₁-C₁₂)alkyl-S—S—(C₁-C₁₂)alkyl, an optionally substituted     carbocyclic or heterocyclic aryl radical, and in particular one of     the radicals represented below

an optionally substituted heterocyclic non aromatic radical, a bis-arylalkyl or di-arylalkyl radical or also the radical

-   Y1 represents O, S, NH or is absent; -   R4 represents (CH₂)_(p)-Z4; -   Z4 represents amino, (C₁-C₁₂)alkyl, (C₃-C₈)cycloalkyl,     (C₁-C₁₂)alkylamino, N,N-di-(C₁-C₁₂)alkylamino,     amino(C₃-C₆)cycloalkyl,     amino(C₁-C₆)alkyl(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, carbocyclic or     heterocyclic aminoaryl, (C₁-C₁₂)alkoxy, (C₁-C₁₂)alkenyl,     N—C(O)O(C₁-C₆)alkyl, an optionally substituted carbocyclic or     heterocyclic aryl radical, an optionally substituted heterocyclic     non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the     radicals represented below

or also Z4 represents an N(R6)(R7) radical in which R6 and R7 taken together with the nitrogen atom which they carry form together a heterocycle with 5 to 7 members;

-   R5 represents H, —(CH₂)_(p)—C(O)—(CH₂)_(p)-Z5, —(CH₂)_(p)-Z5,     —(CH₂)_(p)—OZ5 or —(C₀-C₆)alkyl-C(O)—NH—(CH₂)_(p)-Z5, -   Z5 representing an optionally substituted radical chosen from the     group constituted by the —(C₁-C₁₂)alkyl, benzo[b]thiophene, phenyl,     naphthyl, benzo[b]furannyl, thiophene, isoxazolyl, indolyl radicals,     and

it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃, —OCF₃, (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy, —(CH₂)_(p)-phenyl-(X1)_(q), —NH—CO—(C_(1-C) ₆)alkyl, —NH—C(O)O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —S-phenyl-(X1)_(q), —O—(CH₂)_(p)-phenyl-(X1)_(q), —(CH₂)_(p)—C(O)—O—(C₁-C₆)alkyl, —(CH₂)_(p)—C(O)—(C₁-C₆)alkyl, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)—NH—C₁-C₆)alkyl, —O—(CH ₂)_(p)—N-di-((C₁-C₆)alkyl) and —((C₀-C₁₂))alkyl-(X1)_(q) radicals;

-   X1, each time that it occurs, is independently chosen from the group     constituted by the H, Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃,     —OCF₃, (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy, —S—(C₁-C₆)alkyl,     —(CH₂)_(p)-amino, —(CH₂)_(p)—NH—(C₁-C₆)alkyl,     —(CH₂)_(p)—N-di-((C₁-C₆)alkyl), —(CH₂)_(p) and     —(CH₂)_(p)—NH—(C₃-C₆)cycloalkyl radicals;

p each time that it occurs is independently 0 or an integer from 1 to 6;

q each time that it occurs is independently an integer from 1 to 5.

X represents O or S;

n represents 0 or 1; and finally

when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.

According to a preferred variant of the invention, the compounds of general formula (I) are such that R5 represents H.

The compounds of general formula (I) can, if appropriate, contain more than one asymrnetrical centre. If this happens, the diastereomers or any mixture of diastereomers are also included in the invention. For example, when the compound of general formula (I) has two asymmetrical centres, the invention will include the compounds of general formula (I) of “R,S”, “S,R”, “R,R” and “S,S” configurations, as well as a mixture in whatever proportions of the latter.

In the present invention, the alkyl radicals can be linear or branched. By alkyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, unless specified otherwise, is meant a monocyclic carbon system containing 3 to 7 carbon atoms. By alkenyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system containing at least one aromatic ring, a system being called heterocyclic when at least one of the rings which comprise it contains a heteroatom (O, N or S). By aryl, unless specified otherwise, is meant a carbocyclic system comprising at least one aromatic ring. By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom. By heterocyclic non aromatic radical, is meant a heterocyclic system containing no aromatic ring, at least one of the rings comprising said system containing at least one heteroatom (O, N or S).

By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylamino, alkenyl, alkynyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylmino, alkenyl, alkynyl and aralkyl radicals the alkyl radical of which has the meaning indicated previously.

By N,N-di-(C₁-C₁₂)alkylamino radical, is meant a dialkylamino radical of which the two alkyl radicals substituting the nitrogen atom can have independently 1 to 12 carbon atoms.

By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By cycloalkyl, is meant in particular the cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexyl and cycloheptanyl radicals. By carbocyclic or heterocyclic aryl, is meant in particular the phenyl, naphthyl, pyridinyl, furannyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl, phthalimidyl radicals. By carbocyclic or heterocyclic aralkyl, is meant in particular the benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl, phthalimidoalkyl radicals.

When an arrow emanates from a chemical structure, said arrow indicates the attachment point. For example:

represents the aminoethyl radical.

When an arrow is drawn through a bi- or tricyclic group, said arrow indicates that said bi- or tricyclic group can be attached by any of the available attachment points on any aromatic ring of said group. For example:

represents a radical which is attached at any position on the benzene rinag

In particular, the compounds of general formula (I) according to the invention can be chosen such that:

-   R1 represents an optionally substituted aryl radical; -   R2 represents H or an alkyl radical; -   R3 represents one of the following radicals:

-   R4 represents one of the following radicals:

-   R5 represents H or an alkyl radical.

Preferably, the compounds of general formula (I) are such that:

-   R1 represents the phenyl radical optionally substituted by a halogen     atom or a (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy or nitro radical; -   R2 and R5 represent H or alkyl; -   R3 represents H or (CH₂)_(p)-Z3; -   Z3 represents (C₁-C₁₂)alkyl, (C₃-C₈)cycloalkyl,     Y1-(CH₂)_(p)-phenyl-(X1)_(n), an optionally substituted carbocyclic     or heterocyclic aryl radical, an optionally substituted heterocyclic     non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the     radicals represented below

-   Y1 represents O, S, NH or is absent; -   R4 represents (CH₂)_(p)-Z4; -   Z4 represents amino, (C₃-C₈)cycloalkyl, (C₁-C₁₂)alkylamino,     N,N-di-(C₁-C₁₂)alkylamino, amino(C₃-C₆)cycloalkyl,     amino(C₁-C₆)alkyl(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, carbocyclic or     heterocyclic aminoaryl, an optionally substituted carbocyclic or     heterocyclic aryl radical, an optionally substituted heterocyclic     non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the     radicals represented below

it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃, —OCF₃, (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy, —(CH₂)_(p)-phenyl-(X1)_(q), —NH—CO—(C₁-C₆)alkyl, —NH—C(O)O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —S-phenyl-(X1)_(q), —O—(CH₂)_(p)-phenyl-(X1)_(q), —(CH₂)_(p)—C(O)—O—(C₁-C₆)alkyl, —(CH₂)_(p)—C(O)—(C₁-C₆)alkyl, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)—NH—(C₁-C₆)alkyl, —O—(CH₂)_(p)—N-di-((C₁-C₆)alkyl) and —((C₀-C₁₂))alkyl-(X1)_(q) radicals;

-   X1, each time that it occurs, is independently chosen from the group     constituted by the H, Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃,     —OCF₃, (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy, —S—(C₁-C₆)alkyl,     —(CH₂)_(p)-amino, —(CH₂)_(p)—NH—(C₁-C₆)alkyl,     —(CH₂)_(p)—N-di-((C₁-C₆)alkyl), —(CH₂)_(p)-phenyl and     —(CH₂)_(p)—NH—(C₃-C₆)cycloalkyl radicals;

p each time that it occurs is independently 0 or an integer from 1 to 6;

q each time that it occurs is independently an integer from 1 to 5.

X represents O or S;

n represents 0 or 1; and finally

when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.

More preferentially, the compounds of general formula (I) are such that:

-   R1 represents the phenyl radical optionally substituted by a halogen     atom or a (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy or nitro radical; -   R2 and R5 represent H or alkyl; -   R3 represents (CH₂)_(p)-Z3, -   Z3 representing a (C₃-C₈)cycloalkyl radical or an optionally     substituted radical chosen from the phenyl, naphthyl, furannyl,     thiophene, indolyl, pyrrolyl and benzothiophene radicals; -   R4 represents (CH₂)_(p)-Z4; -   Z4 representing amino, (C₁-C₁₂)alkylamino, N,N-di-(C₁-C₁₂)alkylamino     or amino(C₁-C₆)alkyl(C₃-C₆)cycloakyl—(C₁-C₆)alkyl; -   X represents S; -   p each time that it occurs is independently 0 or an integer from 1     to 6;

m represents 0, 1 or 2; and finally n represents 0 or 1.

Yet more preferentially, the compounds of the present invention are of the compounds:

-   -   of general sub-formula (I)a represented below:

in which:

-   R′3 represents one of the radicals represented below:

and R′4 represents one of the radicals represented below:

-   -   of general sub-formula (I)b represented below:

in which:

-   R′3 represents one of the radicals represented below:

and R′4 represents one of the radicals represented below:

-   -   of general sub-formula (I)c represented below:

in which:

-   R′3 represents one of the radicals represented below:

and R′4 represents one of the radicals represented below:

The invention relates moreover to the preparation processes for the compounds of general formula (I) described previously (also applicable to the corresponding compounds of general sub-formulae (I)a, (I)b and (I)c).

The compounds of general formula (I) described previously for which n represents 0 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (II) represented below

in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the O-GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy, with an isocyanate or isothiocyanate of general formula (III) R4-N═C═X,  (III) in which R4 and X have the same meaning as in general formula (I), preferably in the presence of a tertiary base for a duration of approximately 1 to 24 hours and at a temperature preferably comprised between 20 and 60° C.

The compounds of general formula (I) described previously for which n represents 1 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (IV) represented below

in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the O-GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy, with an isocyanate or isothiocyanate of general formula (III) R4-N═C═X  (III) in which R4 and X have the same meaning as in general formula (I),

preferably in the presence of a tertiary base for a duration of approximately 1 to 48 hours and at a temperature comprised between 20 and 70° C.

For the above processes, the aprotic solvent is preferably polar and can in particular be THF or dichloromethane. The tertiary base will be for example triethylamine or N,N-diisopropylethylamine.

Moreover the invention offers new synthesis intermediates which are useful for the preparation of the compounds of general formula (I). These compounds, precursors of the compounds of general formula (II) and (IV), correspond to general formula (V):

in which

-   R1, R2, R5, m and n have the same meaning as in general formula (I);     and the O-GP radical is a parting protective group derived from an     alcohol and in particular benzyloxy, methoxy or tert-butoxy.

The following compounds corresponding to general formula (V) are the preferred intermediates:

-   - benzyl (2S)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate; -   - benzyl (2R)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate; -   - benzyl (2S)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate; -   - benzyl (2R)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate; -   - benzyl (3R)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate; -   - benzyl (3S)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate.

A subject of the invention is also, as medicaments, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts. It also relates to the pharmaceutical compositions containing said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat the pathological states or diseases in which one (or more) of the somatostatin receptors are involved.

In particular, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, syndrome X, dawn phenomena, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, -enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, diarrhoeas induced by chemotherapy, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, bleeding of grafted vessels, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and in other therapeutic fields, cephaleas including cephalea associated with hypophyseal tumours, pain, inflammatory disorders such as arthritis, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, hyperlipidemia, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, chronic rejection of allografts as well as Alzheimer's disease and finally osteoporosis.

Preferably, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, bypophyseal adenomas or endocrinic gastroenteropancreatic tumours including carcinoid syndrome, and gastrointestinal bleeding.

By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartarate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate and stearate.

The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to “Pharmaceutical salts”, J. Pharm. Sci. 66:1 (1977).

The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water. The suspensions contain in particular suspensions of sustained release microparticles loaded with active ingredient (in particular microparticles of polylactide-co-glycolide or PLGA-cf. for example the U.S. Pat. No. 3,773,919, EP 52 510 or EP 58 481 or the patent application PCT WO 98/47489), which allow the administration of a determined daily dose over a period of several days to several weeks.

The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.

The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg to 10 g according to the type of active compound used.

These compounds are prepared according to the following procedures.

Preparation of the Compounds of the Invention

Preparation of Imidazolyl Derivatives

General Procedure:

i) Cyclization in order to obtain the imidazole group:

An amino acid is converted to its cesium salt using cesium carbonate in a polar solvent such as a DMF/H₂O (1:1) or EtOH/H₂O (1:1) mixture. An ester is then obtained using an appropriate bromoketone in an aprotic polar solvent such as anhydrous DMF. The cesium bromide formed is eliminated by filtration and ammonium acetate is added in an aprotic solvent having a high boiling temperature such as xylene or toluene or in an acidic aprotic solvent such as acetic acid. The mixture is maintained under reflux using a Dean-Stark trap for 30 minutes to one hour. In the diagram directly below, PG1 is a protective group, preferably a carbamate, such as t-Boc or benzylcarbamate, and PG2 is also a protective group, preferably a benzyl group.

ii) N-substitution on the Imidazole Group:

If appropriate, the N-substitution on the imidazole group is carried out by the reaction described hereafter for the compounds of general formula (I) for which R5 does not represent H.

A solution of the intermediate obtained in the preceding stage, an alkylating agent such as an -bromoketone, an -bromoester, an alkyl or aryl bromide, is heated to a temperature of 20 to 80° C. for a duration of 2 to 48 hours in the presence of an organic or inorganic base (optionally supported on a resin such as polystyrene resin), in an aprotic solvent such as THF, acetonitrile or DMF.

Preparation of Benzyl (2S)-2-[(Tert-butoycarbonyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate

A solution of Boc-L-Asp-OBn (12 g; 37.1 mmol) and cesium carbonate (6.05 g; 0.5 eq.) is stirred for approximately 30 minutes at approximately 20° C. in EtOH/H₂O (1:1, 7 ml), then concentrated under reduced pressure at approximately 40° C.

25 ml of a solution of 2-bromoacetophenone (7.38 g; 1 eq.) in dry DMF is added to the resulting salt dissolved in 130 ml of dry DMF. The mixture is stirred for approximately 1 hour at approximately 20° C. under an argon atmosphere then concentrated under reduced pressure. Ethyl acetate is added (100 ml) and the mixture filtered, CsBr being washed with ethyl acetate. The filtrate is then concentrated under reduced pressure. A solution of the residue obtained and ammonium acetate (58 g; 20 eq.) in xylene,(280 ml) is maintained under reflux for approximately 30 minutes at approximately 140° C. The excess NH₄OAc and water are eliminated using a Dean-Stark trap. The progress of the reaction is monitored by thin layer chromatography (TLC; eluent: ethyl acetate/heptane 1:1). The mixture is then taken to approximately 20° C. then washed successively with water, a saturated solution of NaHCO₃ solution until a basic pH is obtained then with salt water until a neutral pH is obtained. The organic phase is then dried over Na₂SO₄ and concentrated under reduced pressure.

Purification of the resulting residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 1:1) yields the expected compound (8.2 g; 52%).

NMR (¹H, 400 MHz, CDCl₃): 7.64-7.14 (m, 11H, arom H); 5.95 (d, 1H, NHBoc); 5.21-5.13 (AB, 2H, OCH₂Ph, J_(AB)=12 Hz); 4.73 (m, 1H, CH); 3.30 (m, 2H, CH₂); 1.42 (s, 9H, (CH₃)₃C).

MS/LC: calculated MM=421.2; m/z=422.2 (M+H).

The following compounds are prepared in an analogous fashion to the procedure described for benzyl (2S)-2-[(tert-butoxycarbonyl)amino)]-3-(4-phenyl-1H-imidazol-2-yl)propanoate:

Deprotection Stage

General procedure: the imidazolyl derivatives protected by N-Boc are treated with an organic or inorganic acid such as trifluoroacetic acid or hydrogen chloride (aqueous or in gaseous form) in an aprotic solvent such as dichloromethane or ethyl acetate at a temperature comprised between 0° C. and 25° C. for 0.5 to 5 hours. Preparation of the Dihydrochloride of Benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-amino-propanoate

A flow of dry HCl is passed through a solution of benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-[(tert-butoxycarbonyl)amino propanoate (5 g) in ethyl acetate (120 ml) at 0° C. until the TLC (eluent: 100% ethyl acetate) shows that the starting compound has completely disappeared. The resulting mixture is then evaporated under reduced pressure. Diethylether is added to the solid obtained and the mixture is filtered. The hydrochloride is washed several times with dichloromethane then diethylether and dried under reduced pressure to produce 4.6 g of expected compound (98% yield).

NMR (¹H, 400 MHz, DMSOd6): 9.21 (broad s, 2H, NH); 8.03-7.28 (m, arom. H, 11H); 5.10 (s, 1H, OCH₂Ph); 5.04 (m, 1H, CH); 3.61 (dd, 1H, CH₂, 3J=9 Hz, 2J=17.0 Hz); 3.39 (dd, 1H, CH₂′, 3J=5.5 Hz, 2J=17.0 Hz).

MS/LC: Calculated MM=321.2; m/z=322.1 (M+H).

The following compounds are prepared in an analogous fashion to the procedure described for the dihydrochloride of benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-amino-propanoate.

N-Alkylation Reaction

General procedure: A free amine of formula (a) or (b) is treated with an aldehyde in a protic or aprotic solvent, preferably dichloromethane or tetrahydrofuran, for a duration of 1 to 15 hours at 20-50° C. The resulting imine is then reduced using a reducing agent, preferably sodium triacetoxyborohydride or sodium cyanoborohydride with or without the presence of an acid such as acetic acid, at a temperature comprised between 20 and 50° C. for a duration of 0.2 to 5 hours. The N-alkylated compound is isolated by adding water and extraction followed by flash chromatography on silica gel or by crystallization. Preparation of Benzyl (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate

Thiophene-3-carboxaldehyde (1 ml; 1 eq.) is added to a solution of benzyl (2S)-2-amino-4-(4-phenyl-1H-imidazol-2yl)butanoate in the form of a free base (3.6 g; 1 eq.) in tetrahydrofuran (hereafter THF, 40 ml). The mixture is stirred for 15 hours at approximately 20° C. and diluted by adding 50 ml of tetrahydrofuran. NaBH(OAc)₃ (4.73 g; 2 eq.) is then added. After 1 hour of stirring at approximately 20° C., the reaction is stopped by adding water (40 ml) and ethyl acetate is then added (100 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na₂SO₄ then evaporated under reduced pressure at 40° C. Flash chromatography purification on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound in the form of a yellow oil (3.08 g; 66% yield).

NMR (¹H, 400 MHz, CDCl₃): 7.62-7.04 (m, 15H, arom. H, NH); 5.18 (s, 2H, OCH₂); 3.87-3.69 (AB, 2H, CH₂NH, 2J_(AB)=13 Hz); 3.38 (dd, 1H, CHNH, 3J=4.5 Hz, 2j=8.5 Hz); 2.98 (m, 1H, CH₂CH); 2.88 (m, 1H, CH₂CH); 2.17 (m, 1H, CH₂); 1.97 (m, 1H, CH₂).

MS/LC: Calculated MM=431.2; m/z=432.2 (M+H); m/z=430.8 (M−H).

The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for benzyl (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethy]butanoate:

In the above formulae, R3 represents one of the following radicals:

Preparation of Hydantoins and Thiodydantoins

General Procedure:

An amine of formula (II), in which m, R1, R2, R3 and R5 have the same meanings as in general formula (I) and the O-GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or a isothiocyanate of general formula R4-NCX in which R4 has the same meaning as in general formula (I), in the presence or in the absence of a tertiary base such as triethylamine or N,N-diisopropylethylamine, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, at a temperature comprised between approximately 20 and 60° C. and for 1 to 24 hours. The resulting hydantoin or thiohydandoin can be isolated with a yield of 60 to 95%, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.

When R4 represents a radical comprising a primary amino termination (for example R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4-NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).

Preparation of Certain Non-Commercial Isothiocyanates of General Formula (III):

These compounds are prepared as follows: a primary amine of general formula R4-NH₂ is treated with a mixture of carbon disulphide and N-cyclohexylcarbodiimide N-methyl polystyrene resin, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, for a duration of 1 hour to 18 hours at 20-50° C. The resulting isothiocyanate is isolated after filtration on frit and evaporation of the filtrate.

Preparation of 6-isothiocyanato-N,N-dimethyl-1-hexanamine

Carbon disulphide (8.3 mL, 10 eq) and a solution of N,N-dimethyl-1,6-hexanediamine (2 g, 1 eq) in THF (10 mL) are added successively dropwise to a suspension of N-cyclohexylcarbodiimide N-methyl polystyrene resin (7.8 g, 1.1 eq; acquired from Novabiochem, load 1.95 mmol/g) in anhydrous THF (120 mL). The suspension is stirred for 2 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. in order to produce the expected isothiocyanate derivative (2.6 g, 93% yield).

NMR ¹H, 400 MHz, CDCl₃, ): 3.50 (t, 2H); 2.24 (t, 2H), 2.20 (s, 6H), 1.68 (q, 2H), 1.50-1.31 (m, 6H).

The following compounds are prepared in an analogous fashion to the procedure described for 6-isothiocyanato-N,N-dimethyl-1-hexanamine:

Preparation of (5S)-1-(1H-indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-2thioxo-4imidazolidinone

4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3ylmethyl)amino]-4(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).

NMR (¹H, 400 MHz, CDCl₃): 8.24-7.09 (m, 17H, arom H, NH); 5.88, 4.64 (AB, 2H, CH₂N, 2J_(AB)=15 Hz); 3.38 (dd, 1H, CH, 3J=3.0 Hz, 2J=8.5 Hz); 2.92 (m, 2H, CH₂CH); 2.74 (m, 1H, CH₂); 2.24 (m, 1H, CH₂).

MS/LC: Calculated MM=536.2; m/z=537.1 (M+H).

The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-1-(1H-indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4phenyl-1H-imidazol-2-yl)ethyl]2-thioxo-4-imidazolidinone (apart from the final purification by flash chromatography on silica gel which is optional):

In the above formulae, R3 represents one of the following radicals:

and R4 represents one of the following radicals:

Preparation of (5S)-1-(1H-indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione

3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (23 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 2 hours at approximately 20° C. then diluted with 2 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine) in order to produce the expected compound (25 mg, 92% yield).

NMR (¹H, 400 MHz, CDCl₃): 7.75-6.99 (m, 17H, arom H, NH); 5.25, 4.44 (AB, 2H, CH₂N, J_(AB)=15 Hz); 3.77 (m, 1H, CH); 2.92 (m, 1H, CH₂CH); 2.88 (m, 1H, CH₂CH); 2.72 (m, 1H, CH₂); 2.17 (m, 1H, CH₂).

MS/LC: Calculated MM=543.2; m/z=544.2 (M+H).

The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-1-(1H-indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4imidazolidinedione:

In the above formulae, R3 represents one of the following radicals:

and R4 represents one of the following radicals:

Preparation of Dihydropyrimidine-2,4-diones and 2-thioxo-tetrahydro-4-pyrimidinones

General Procedure:

An amine of general formula (IV), in which m, R1, R2, R3 and R5 have the same meanings as in general formula (I) and the O-GP radical is a parting protective group derived from alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or isothiocyanate R4-NCX in the presence of a tertiary base such as triethylamine or N,N-diisopropylethylamine in an aprotic solvent, preferably THF or dichloromethane, at a temperature comprised between 20 and 70° C. for 1 to 48 hours. The compound obtained can be isolated with a yield of 40 to 90%, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.

When R4 represents a radical comprising a primary amino termination (for example R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4-NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).

Preparation of (6S)-1-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-thioxotetrahydro-4(1H)-pyrimidinone

Propylisothiocyanate (25 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3(4phenyl-1H-imidazol-2-yl)propanoate (90 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added. The mixture is stirred for 5 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 1 ml of THF and 1 ml of triethylamine are added to the residue. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2)-yields the expected compound (72 mg, yield 82%).

NMR (¹H, 400 MHz, CDCl₃): mixture of 2 atropisomers: 8.69-6.45 (m, 12H, H arom, NH); 6.42, 4.89 (AB, 1H, CH₂, J_(AB)=14.5 Hz); 5.78, 5.42 (AB, 1H, CH₂, J_(AB)=14.5 Hz); 4.99 (m, 1H, CH); 4.41-4.36 (m, 1H, CH₂); 4.20-4.11 (m, 1H, CH₂); 3.49, 2.94 (AB, 1H, CH₂CO, J_(AB)=16 Hz); 3.28, 2.80 (AB, 1H, CH₂CO, J_(AB=)16 Hz); 1.52 (m, 1H, CH₂); 1.40 (m, 1H, CH₂); 0.76, 0.62 (2m, 3H, CH₃).

MS/LC: Calculated MM=443.2; m/z=444.2 (M+H).

The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-thioxotetrahydro-4(1H)-pyrimidinone (except for the final purification by flash chromatography on silica gel which is optional):

In the above formula, R3 represents one of the following radicals:

and R4 represents one of the following radicals:

Preparation of (6S)-1-(1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H -imidazol-2-yl)dihydro-2,4(1H,3H)-pyimidinedione

4-methoxyphenylisocyanate (40 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (100 mg, 1 eq.) in THF (2 ml). The mixture is stirred for 5 hours at a temperature of approximately 20° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 138 mg, 2 eq.) is added. The mixture is stirred for 3 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 2 ml of THF and 2 ml of triethylamine are added to the residue. The mixture is taken to reflux for 24 hours then concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) yields the expected compound (80 mg, yield 74%).

NMR (¹H, 400 MHz, CDCl₃): mixture of 2 atropisomers: 9.67-8.96 (2s, 1H, NH); 8.49 (s, 1H, NH); 5.15, 4.36 (AB, 1H, CH₂, J_(AB)=15 Hz); 5.08, 4.69 (AB, 1H, CH₂, J_(AB)=15 Hz); 4.67, 4.57 (2m, 1H, CH); 3.72 (s, 3H, OCH₃); 3.29-2.79 (m, 2H, CH₂CO).

MS/LC: Calculated MM=491.2; m/z=492.3 (M+H).

The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2.4(1H,3H)-pyrimidinedione (except for the final purification by flash chromatography on silica gel which is optional):

In the above formula, R3 represents one of the following radicals:

and R4 represents one of the following radicals:

EXAMPLES

The examples prepared according to the synthesis methods described above are shown in tables below. These examples are presented to illustrate the above procedures and should in no case be considered as limiting the scope of the invention.

Analytical Methods used for the Characterization of the Compounds

The compounds obtained have been characterized according to their retention time (rt) and to their mass spectrometry (MH+).

) Mass Spectrometry

For the mass spectrometry, a single quadrupole mass spectrometer (Micromass, platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50% valley.

Calibration is carried out monthly between the masses 80 and 1000 Da using a calibration mixture of sodium and rubidium iodide in solution in an isopropanol/water mixture ( 1/1 Vol.).

) High Performance Liquid Chromatography (HPLC)

For the liquid chromatography, an HPLC HP1100 system (Hewlett-Packard) including an in-line degasser, a quatemary pump, a column oven and a diode array UV detector is used.

Different elution conditions are used according to the examples:

Conditions (i):

-   -   Eluants:         -   A water+0.04% trifluoroacetic acid         -   B acetonitrile

T (min) A % B % 0 100 0 1 100 0 8 30 70 10 30 70

Flow rate: 1.1 ml/min

Injection: 5 μl

Column: Uptisphere ODS 3 μm 33*4.6 mm i.d.

Temperature: 40° C.

Conditions (ii):

-   -   Eluants:         -   A water+0.04% trifluoroacetic acid         -   B acetonitrile

T (min) A % B % 0 90 10 6 15 85 10 15 85

Flow rate: 1 ml/min

Injection: 5 μl

Column: Uptisphere ODS 3 μm 50*4.6 mm i.d.

Temperature: 40° C.

Elution conditions (i) are used for the characterization of Examples 1 to 479, 560 to 572 and 733 to 1040. As regards conditions (ii) they are used for Examples 480 to 559, 573 to 732 and 1041 to 1234. The UV detection is carried out at a wavelength of 220 nm for all the examples.

Analyses Ex. No. Formula R1 R2 Purity rt (min) [M + H]⁺ 1 C29H25N5O2

89.6% 6.2 476.2 2 C30H27N5O2

91.0% 6.4 490.3 3 C30H27N5O3

90.1% 6.2 506.3 4 C30H27N5O2S

91.0% 6.6 522.2 5 C30H24F3N5O3

83.1% 7.0 560.2 6 C32H31N5O2

84.9% 7.0 518.3 7 C29H24BrN5O2

81.9% 6.7 556.1 8 C29H24ClN5O2

79.1% 6.6 510.2 9 C29H24N6O4

87.3% 6.4 521.2 10 C35H37N5O2

94.1% 7.3 560.3 11 C29H23F2NSO2

96.9% 6.3 512.2 12 C30H27N5O2

96.3% 6.4 490.2 13 C31H29N5O2

92.0% 6.5 504.2 14 C29H31N5O2

85.7% 6.6 482.3 15 C26H27N5O2

94.2% 5.9 442.3 16 C27H29N5O2

91.7% 6.3 456.3 17 C26H25N5O2

96.6% 5.8 440.2 18 C28H31N5O2

87.2% 6.6 470.3 19 C26H27N5O2

89.1% 6.0 442.2 20 C32H31N5O5

80.5% 6.1 566.2 21 C25H22N4O2S

92.3% 5.9 443.2 22 C26H24N4O2S

90.2% 6.2 457.2 23 C26H24N4O3S

92.1% 6.0 473.2 24 C26H24N4O2S2

92.8% 6.4 489.2 25 C26H21F3N4O3S

87.7% 6.8 527.2 26 C28H28N4O2S

87.8% 6.8 485.3 27 C25H21BrN4O2S

84.3% 6.5 523.1 28 C25H21ClN4O2S

84.9% 6.4 477.2 29 C25H21N5O4S

94.0% 6.2 488.2 30 C31H34N4O2S

97.2% 7.2 527.3 31 C25H20F2N4O2S

96.7% 6.1 479.2 32 C26H24N4O2S

95.3% 6.2 457.2 33 C27H26N4O2S

93.0% 6.4 471.2 34 C25H28N4O2S

88.3% 6.4 449.2 35 C22H24N4O2S

90.8% 5.7 409.2 36 C23H26N4O2S

91.8% 6.1 423.2 37 C22H22N4O2S

97.9% 5.6 407.2 38 C24H28N4O2S

84.3% 6.4 437.2 39 C22H24N4O2S

87.2% 5.7 409.2 40 C28H28N4O5S

92.2% 5.9 533.2 41 C28H26N4O3

93.9% 6.1 467.2 42 C29H28N4O3

95.8% 6.3 481.3 43 C29H28N4O4

93.0% 6.1 497.3 44 C29H28N4O3S

94.5% 6.5 513.2 45 C29H25F3N4O4

90.4% 6.9 551.2 46 C31H32N4O3

87.7% 6.9 509.3 47 C28H25BrN4O3

84.2% 6.6 547.1 48 C28H25ClN4O3

86.6% 6.5 501.2 49 C28H25N5O5

93.9% 6.3 512.2 50 C34H38N4O3

98.3% 7.2 551.3 51 C28H24F2N4O3

98.0% 6.2 503.2 52 C29H28N4O3

94.6% 6.4 481.2 53 C30H30N4O3

91.5% 6.4 495.3 54 C28H32N4O3

85.8% 6.5 473.3 55 C25H28N4O3

89.7% 5.8 433.3 56 C26H30N4O3

90.6% 6.2 447.3 57 C25H26N4O3

97.1% 5.7 431.2 58 C27H32N4O3

75.3% 6.5 461.3 59 C25H28N4O3

86.1% 5.9 433.3 60 C31H32N4O6

83.5% 6.0 557.2 61 C29H29N5O2

92.62%* 5.3 480.3 62 C30H31N5O2

93.25%* 5.6 494.3 63 C30H31N5O3

94.39%* 5.4 510.3 64 C30H31N5O2S

95.36%* 5.8 526.3 65 C30H28F3N5O3

89.2% 6.3 564.2 66 C32H35N5O2

86.35%* 6.3 522.3 67 C29H28BrN5O2

84.14%* 5.9 560.1 68 C29H28ClN5O2

85.8% 5.8 514.2 69 C29H28N6O4

94.4% 5.6 525.3 70 C35H41N5O2

95.76%* 6.8 564.3 71 C29H27F2N5O2

96.29%* 5.5 516.3 72 C30H31N5O2

97.59%* 5.6 494.3 73 C31H33N5O2

94.87%* 5.7 508.3 74 C29H35N5O2

87.63%* 5.8 486.3 75 C26H31N5O2

87.69%* 5.0 446.3 76 C27H33N5O2

86.66%* 5.4 460.3 77 C26H29N5O2

93.78%* 4.9 444.3 78 C28H35N5O2

85%* 5.8 474.3 79 C26H31N5O2

87.49%* 5.0 446.3 80 C32H35N5O5

87.6% 5.3 570.3

Analyses Ex. No. Formula R1 R2 Purity rt (min) [M + H]⁺ 81 C28H23N5O2

92% 6.2 462.2 82 C29H25N5O2

93% 6.5 476.2 83 C29H25N5O3

94% 6.2 492.2 84 C29H25N5O2S

92% 6.6 508.2 85 C29H22F3N5O3

92% 7.0 546.2 86 C31H29N5O2

92% 7.1 504.3 87 C28H22BrN5O2

92% 6.8 542.1 88 C28H22ClN5O2

92% 6.7 496.2 89 C28H22N6O4

82% 6.5 507.2 90 C34H35N5O2

92% 7.3 546.3 91 C28H21F2N5O2

90% 6.2 498.2 92 C31H29N5O5

82% 6.2 552.2 93 C29H22F3N5O2

92% 6.9 530.2 94 C30H25N5O3

89% 6.1 504.2 95 C29H25N5O2

92% 6.4 476.2 96 C30H27N5O2

93% 6.6 490.3 97 C25H25N5O2

95% 5.9 428.2 98 C26H27N5O2

95% 6.3 442.3 99 C25H23N5O2

95% 5.8 426.2 100 C27H29N5O2

94% 6.6 456.3 101 C24H20N4O2S

92% 5.9 429.2 102 C25H22N4O2S

91% 6.2 443.2 103 C25H22N4O3S

90% 6.0 459.2 104 C25H22N4O2S2

87% 6.4 475.2 105 C25H19F3N4O3S

89% 6.8 513.2 106 C27H26N4O2S

89% 6.9 471.2 107 C24H19BrN4O2S

91% 6.5 509.1 108 C24H19C1N4O2S

90% 6.4 463.1 109 C24H19N5O4S

76% 6.3 474.2 110 C30H32N4O2S

90% 7.1 513.3 111 C24H18F2N4O2S

82% 6.0 465.2 112 C27H26N4O5S

77% 5.8 519.2 113 C25H19F3N4O2S

89% 6.7 497.2 114 C26H22N4O3S

86% 5.8 471.2 115 C25H22N4O2S

85% 6.1 443.2 116 C26H24N4O2S

82% 6.3 457.2 117 C21H22N4O2S

84% 5.6 395.2 118 C22H24N4O2S

93% 5.9 409.2 119 C21H20N4O2S

89% 5.4 393.2 120 C23H26N4O2S

81% 6.3 423.2 121 C27H24N4O3

91% 6.0 453.2 122 C28H26N4O3

92% 6.3 467.2 123 C28H26N4O4

91% 6.0 483.3 124 C28H26N4O3S

88% 6.4 499.2 125 C28H23F3N4O4

91% 6.9 537.2 126 C30H30N4O3

90% 6.9 495.2 127 C27H23BrN4O3

89% 6.6 533.1 128 C27H23ClN4O3

91% 6.5 487.2 129 C27H23N5O5

75% 6.4 498.2 130 C33H36N4O3

90% 7.2 537.3 131 C27H22F2N4O3

82% 6.1 489.2 132 C30H30N4O6

79% 6.0 543.2 133 C28H23F3N4O3

90% 6.8 521.2 134 C29H26N4O4

85% 5.9 495.2 135 C28H26N4O3

89% 6.2 467.2 136 C29H28N4O3

89% 6.4 481.2 137 C24H26N4O3

88% 5.7 419.3 138 C25H28N4O3

90% 6.1 433.3 139 C24H24N4O3

92% 5.6 417.3 140 C26H30N4O3

87% 6.4 447.3 141 C28H27N5O2

89% 5.1 466.2 142 C29H29N5O2

89% 5.5 480.3 143 C29H29N5O3

90% 5.2 496.3 144 C29H29N5O2S

86% 5.7 512.2 145 C29H26F3N5O3

87% 6.2 550.2 146 C31H33N5O2

87% 6.2 508.3 147 C28H268rNSO2

88% 5.8 546.1 148 C28H26ClN5O2

88% 5.7 500.2 149 C28H26N6O4

74.76%* 5.6 511.2 150 C34H39N5O2

85% 6.7 550.3 151 C28H25F2N5O2

81% 5.3 502.2 152 C31H33N5O5

79% 5.2 556.3 153 C29H26F3N5O2

88% 6.1 534.2 154 C30H29N5O3

85% 5.1 508.3 155 C29H29N5O2

86% 5.4 480.3 156 C30H31N5O2

86% 5.6 494.3 157 C25H29N5O2

85% 4.8 432.3 158 C26H31N5O2

84% 5.2 446.3 159 C25H27N5O2

86% 4.7 430.3 160 C27H33N5O2

88% 5.6 460.3

Analyses Ex. No. Formula R1 R2 Purity rt (min) [M + H]⁺ 161 C30H27N5OS

80% 7.1 506.2 162 C30H26ClN5OS

83% 7.3 540.2 163 C30H25Cl2N5OS

81% 7.7 574.1 164 C31H27N5O3S

81% 7.0 550.2 165 C30H26FN5OS

82% 7.1 524.3 166 C31H29N5OS

81% 7.3 520.3 167 C31H28ClN5OS

83% 7.6 554.2 168 C33H33N5O3S

80% 7.0 580.3 169 C32H31N5OS

78% 7.4 534.3 170 C28H25N5O2S

85% 6.7 496.3 171 C28H29N5O2S

81% 6.6 500.3 172 C28H29N5OS

71% 7.1 484.3 173 C29H31N5OS

61% 7.3 498.3 174 C30H33N5OS

64% 7.6 512.3 175 C29H32N6O2S

84% 5.0 529.3 176 C30H34N6O2S

86% 5.0 543.3 177 C30H36N6OS

83% 5.2 529.3 178 C26H27N5O2S

82% 6.3 474.3 179 C27H29N5O2S

80% 6.4 438.3 180 C27H29N5OS

74% 7.0 472.3 181 C26H24N4OS2

77% 6.9 473.2 182 C26H23ClN4OS2

78% 7.1 507.2 183 C26H22Cl2N4OS2

84% 7.6 541.1 184 C27H24N4O3S2

80% 6.9 517.2 185 C26H23FN4OS2

75% 7.0 491.2 186 C27H26N4OS2

80% 7.1 487.2 187 C27H25ClN4OS2

85% 7.4 521.2 188 C29H30N4O3S2

87% 6.8 547.2 189 C28H28N4OS2

77% 7.3 501.2 190 C24H22N4O2S2

86% 6.5 463.2 191 C24H26N4O2S2

58.9% +19.6% 6.4 467.2 192 C24H26N4OS2

75% 6.9 451.2 193 C25H28N4OS2

77% 7.2 465.2 194 C26H30N4OS2

76% 7.5 479.3 195 C25H29N5O2S2

81% 4.8 496.3 196 C26H31N5O2S2

82% 4.9 510.3 197 C26H33N5OS2

71% 5.0 496.3 198 C22H24N4O2S2

81% 6.1 441.2 199 C23H25N4O2S2

78% 6.2 455.2 200 C23H26N4OS2

79% 6.8 551.2 201 C29H28N4O2S

80% 7.0 497.3 202 C29H27ClN4O2S

81% 7.2 643.2 203 C29H26Cl2N4O2S

86% 7.6 677.2 204 C30H28N4O4S

82% 7.0 653.2 205 C29H27FN4O2S

72% 7.1 627.2 206 C30H30N4O2S

83% 7.2 511.3 207 C30H29ClN4O2S

87% 7.5 657.2 208 C32H34N4O4S

87% 6.9 571.3 209 C31H32N4O2S

83% 7.4 637.3 210 C27H26N4O3S

87% 6.6 599.2 211 C27H30N4O3S

59% +20% 6.5 + 6.6 491.2 212 C27H30N4O2S

81% 7.0 475.5 213 C28H32N4O2S

82% 7.2 601.2 214 C29H34N4O2S

83% 7.5 615.3 215 C28H33N5O3S

86% 5.0 520.3 216 C29H35N5O3S

86% 5.0 646.3 217 C29H37N5O2S

78% 5.1 632.3 218 C25H28N4O3S

87% 6.2 577.2 219 C26H30N4O3S

80% 6.4 591.3 220 C26H30N4O2S

85% 6.9 575.2 221 C30H31N5OS

77% 6.5 510.3 222 C30H30ClN5OS

66% 6.8 544.3 223 C30H29Cl2N5OS

69% 7.3 690.2 224 C31H31N5O3S

75% 6.4 666.3 225 C30H30FNSOS

52% 6.6 528.5 226 C31H33N5OS

82% 6.7 636.3 227 C31H32ClN5OS

85% 7.1 670.3 228 C33H37N5O3S

82% 6.4 696.3 229 C32H35N5OS

66% 7.0 650.3 230 C28H29N5O2S

77% 6.1 612.2 231 C28H33N5O2S

26% + 48 5.8 + 5.9 616.3 232 C28H33N5OS

76% 6.4 600.3 233 C29H35N5OS

78% 6.7 614.3 234 C30H37N5OS

77% 4.6 645.3 235 C29H36N6O2S

85% 4.6 659.4 236 C30H38N6O2S

84% 4.8 532.3 237 C30H40N5OS

36% 5.5 590.3 238 C26H31N5O2S

79% 5.7 492.3 239 C27H33N5O2S

69% 6.3 588.3 240 C27H33N5OS

78% 6.3 476.3

Analyses Ex. No. Formula m R1 R2 Purity rt (min) [M + H]⁺ 241 C29H25N5OS 2

93% 6.7 492.2 242 C31H27N5O2S 2

87% 6.6 534.2 243 C35H37N5OS2 2

68% 7.9 576.3 244 C32H31N5OS 2

88% 7.5 534.2 245 C29H23F2N5OS 2

92% 6.9 528.2 246 C29H24FN5OS 2

92% 6.8 510.2 247 C29H22Cl3N5OS 2

82% 7.6 594.1 248 C29H23Cl2N5OS 2

86% 7.5 560.1 249 C29H22Br3N5OS 2

76% 7.8 725.9 250 C31H29N5OS 2

47% 7.1 520.2 251 C31H23F6N5OS 2

88% 7.8 628.2 252 C30H24F3N5OS 2

90% 7.3 560.2 253 C31H29N5O3S 2

86% 6.9 552.2 254 C30H27N5O2S 2

93% 6.8 522.2 255 C30H27N5OS2 2

88% 7.1 538.2 256 C29H24N6O3S 2

92% 6.9 537.2 257 C29H24N8OS 2

92% 7.1 533.2 258 C31H30N6OS 2

67% 6.7 268.2 259 C30H24N6OS 2

82% 6.7 517.2 260 C36H31N5O2S 2

85% 7.6 598.2 261 C29H29N5OS 2

78% 6.1 248.7 262 C31H31N5O2S 2

65% 6.0 269.7 263 C35H41N5OS 2

53% 7.5 290.8 264 C32H35N5OS 2

82% 7.0 269.8 265 C29H27F2N5OS 2

79% 6.4 266.7 266 C29H28FN5OS2 2

73% 6.2 257.7 267 C29H26Cl3N5OS 2

87% 7.2 299.6 268 C29H27Cl2N5OS 2

70% 7.1 282.6 269 C29H26Br3N5OS 2

78% 7.3 365.5 270 C31H33N5OS2 2

3% 6.6 262.7 271 C31H27F6N5OS 2

39% 7.5 316.8 272 C30H28F3N5OS 2

64% 6.9 282.7 273 C31H33N5O3S 2

78% 6.3 278.7 274 C30H31N5O2S 2

45% 6.2 263.7 275 C30H31N5OS2 2

66% 6.5 271.7 276 C29H28N6O3S 2

67% 6.4 271.2 277 C29H28N8OS 2

62% 6.5 269.2 278 C31H34N6OS 2

37% 6.1 270.2 279 C30H28N6OS 2

49% 6.1 261.3 280 C36H35N5O2S 2

73% 7.2 301.8 281 C24H20N4OS2 1

89% 6.6 445.1 282 C26H22N4O2S2 1

88% 6.6 487.2 283 C30H32N4OS2 1

86% 7.9 529.2 284 C27H26N4OS2 1

96% 7.5 487.2 285 C24H18F2N4OS2 1

93% 6.7 481.1 286 C24H19FN4OS2 1

90% 6.8 463.1 287 C24H17Cl3N4OS2 1

97% 7.5 547.0 288 C24H18Cl2N4OS2 1

90% 7.8 513.1 289 C24H17Br3N4OS2 1

92% 7.7 678.9 290 C26H24N4OS2 1

87% 7.0 473.2 291 C26H18F6N4OS2 1

91% 8.2 581.1 292 C25H19F3N4OS2 1

87% 7.5 513.1 293 C26H24N4O3S2 1

95% 6.8 505.2 294 C25H22N4O2S2 1

92% 6.7 475.1 295 C25H22N4OS3 1

89% 7.1 491.1 296 C24H19N5O3S2 1

88% 7.0 490.1 297 C24H19N7OS2 1

90% 7.1 486.2 298 C26H25N5OS2 1

86% 6.6 244.7 299 C25H19N5OS2 1

89% 6.8 470.1 300 C31H26N4O2S2 1

88% 7.7 551.2 301 C27H24N4O2S 1

92% 6.7 459.2 302 C29H26N4O3S 1

91% 6.7 511.2 303 C33H36N4O2S 1

89% 8.0 553.3 304 C30H30N4O2S 1

95% 7.6 511.2 305 C27H22F2N4O2S 1

95% 6.8 505.2 306 C27H23FN4O2S 1

93% 6.9 487.2 307 C27H21Cl3N4O2S 1

93% 7.6 571.1 308 C27H22Cl2N4O2S 1

85% 7.9 537.1 309 C27H21Br3N4O2S 1

93% 7.8 702.9 310 C29H28N4O2S 1

86% 7.1 497.2 311 C29H22F6N4O2S 1

93% 8.3 605.2 312 C28H23F3N4O2S 1

93% 7.5 537.1 313 C29H28N4O4S 1

96% 6.9 529.2 314 C28H26N4O3S 1

97% 6.8 499.2 315 C28H26N4O2S2 1

84% 7.2 515.2 316 C27H23N5O4S 1

88% 7.1 514.2 317 C27H23N7O2S 1

94% 7.2 510.2 318 C29H29N5O2S 1

89% 6.7 256.7 319 C28H23N5O2S 1

90% 6.8 494.2 320 C34H30N4O3S 1

89% 7.7 575.2

Analyses Ex. No. Formula R1 R2 Purity rt (min) [M + H]+ 321 C29H25N5OS

91 7.2 492.2 322 C29H24ClN5OS

91 7.5 526.2 323 C29H23Cl2N5OS

91 7.9 560.1 324 C30H25N5O3S

92 7.0 536.2 325 C29H24FN5OS

93 7.3 510.2 326 C3OH27N5OS

92 7.4 506.2 327 C30H26ClN5OS

91 7.8 540.2 328 C32H31N5O3S

90 7.1 566.2 329 C31H29N5OS

91 7.6 520.2 330 C27H23N5O2S

92 6.8 482.2 331 C27H27N5O2S

35 + 51 6.64 + 6.76 486.2 332 C27H27N5OS

90 7.2 470.2 333 C28H29N5OS

89 7.4 484.3 334 C29H31N5OS

90 7.7 498.3 335 C28H30N6O2S

94 5.2 258.3 336 C29H32N6O2S

93 5.1 265.3 353 C24H26N4OS2

84 7.3 451.2 354 C25H28N4OS2

86 7.5 465.2 355 C24H27N5O2S2

91 5.0 241.7 356 C25H29N5O2S2

88 5.0 248.8 357 C25H31N5OS2

61 5.1 241.8 358 C21H22N4O2S2

88 6.1 427.1 359 C22H24N4O2S2

87 6.3 441.1 360 C22H24N4OS2

84 6.9 425.2 361 C28H26N4O2S

89 7.1 483.2 362 C28H25ClN4O2S

89 7.5 517.2 363 C28H24Cl2N4O2S

91 7.8 551.1 364 C29H26N4O4S

89 7.0 527.2 365 C28H25FN4O2S

95 7.2 501.2 366 C29H28N4O2S

90 7.3 497.2 367 C29H27ClN4O2S

89 7.7 531.2 368 C31H32N4O4S

90 7.0 557.2 369 C30H30N4O2S

91 7.5 511.2 370 C26H24N4O3S

92 6.7 473.2 371 C26H28N4O3S

39 + 45 6.44 + 6.56 477.2 372 C26H28N4O2S

89 7.1 461.2 373 C27H30N4O2S

90 7.3 475.2 374 C28H32N4O2S

90 7.6 489.3 375 C27H31N5O3S

93 5.1 253.7 376 C28H33N5O3S

90 5.1 260.8 377 C28H35N5O2S

73 5.3 253.8 378 C24H26N4O3S

91 6.2 451.2 379 C25H28N4O3S

91 6.4 465.2 380 C25H28N4O2S

90 7.0 449.2 381 C29H29N5OS

85 6.4 248.7 382 C29H28ClN5OS

85 6.9 265.7 383 C29H27Cl2N5OS

84 7.3 282.6 384 C30H29N5O3S

85 6.3 270.7 385 C29H28FN5OS

88 6.5 257.7 386 C30H31N5OS

84 6.7 255.6 387 C30H30ClN5OS

87 7.2 272.7 388 C32H35N5O3S

82 6.4 285.8 389 C31H33N5OS

81 6.9 262.7 390 C27H27N5O2S

89 5.9 243.7 391 C27H31N5O2S

43 + 43 5.68 + 5.86 245.7 392 C27H31N5OS

83 6.4 237.7 393 C28H33N5OS

83 6.7 244.7 394 C29H35N5OS

85 7.0 251.7 395 C28H34N6O2S

87 4.6 259.8 396 C29H36N6O2S

84 4.6 267.2 397 C25H29N5O2S

74 5.4 232.7 398 C26H31N5O2S

83 5.6 239.7 399 C26H31N5OS

87 6.3 231.8

Analyses Ex. No. Formula m R1 R2 Purity rt (min) [M + H]+ 400 C30H34N6O3S 2

83% 7.8 559.2 401 C31H36N6O3S 2

82% 7.9 573.2 402 C32H38N6O3S 2

82% 8.0 587.3 403 C33H40N6O3S 2

81% 8.3 601.3 404 C34H42N6O3S 2

80% 8.5 615.3 405 C26H31N5O3S2 2

81% 7.6 526.2 406 C27H33N5O3S2 2

83% 7.8 540.2 407 C28H35N5O3S2 2

88% 7.9 554.2 408 C29H37N5O3S2 2

86% 8.2 568.2 409 C30H39N5O3S2 2

86% 8.4 582.3 410 C29H35N5O4S 2

87% 7.7 550.3 411 C30H37N5O4S 2

87% 7.9 564.3 412 C31H39N5O4S 2

92% 8.0 578.3 413 C32H41N5O4S 2

89% 8.3 592.3 414 C33H43N5O4S 2

88% 8.5 606.3 415 C30H38N6O3S 2

83% 7.0 563.3 416 C31H40N6O3S 2

85% 7.2 577.3 417 C32H42N6O3S 2

88% 7.4 591.3 418 C33H44N6O3S 2

88% 7.7 303.3 419 C34H46N6O3S 2

88% 7.9 310.4 420 C29H32N6O3S 2

78% 7.9 545.2 421 C30H34N6O3S 2

81% 8.0 559.2 422 C31H36N6O3S 2

84% 8.1 573.3 423 C32H38N6O3S 2

82% 8.3 587.3 424 C33H40N6O3S 2

86% 8.5 601.3 425 C25H29N5O3S2 2

80% 7.7 512.2 426 C26H31N5O3S2 2

82% 7.8 526.2 427 C27H33N5O3S2 2

87% 7.9 540.2 428 C28H35N5O3S2 2

86% 8.2 554.2 429 C29H37N5O3S2 2

84% 8.4 568.2 430 C28H33N5O4S 2

86% 7.8 536.3 431 C29H35N5O4S 2

85% 7.9 550.3 432 C30H37N5O4S 2

92% 8.0 564.3 433 C31H39N5O4S 2

90% 8.2 578.3 434 C32H41N5O4S 2

90% 8.5 592.3 435 C29H36N6O3S 2

80% 6.9 549.3 436 C30H38N6O3S 2

78% 7.1 563.3 437 C31H40N6O3S 2

84% 7.3 577.3 438 C32H42N6O3S 2

83% 7.5 296.3 439 C33H44N6O3S 2

85% 7.8 303.3 440 C25H26N6OS 1

76% 5.4 459.2 441 C26H28N6OS 1

61% 5.4 473.3 442 C27H30N6OS 1

75% 5.6 244.2 443 C28H32N6OS 1

32% 5.7 251.1 444 C29H34N6OS 1

59% 5.9 258.3 445 C21H23N5OS2 1

78% 5.1 426.2 446 C22H25N5OS2 1

79% 5.2 440.2 447 C23H27N5OS2 1

84% 5.4 227.6 448 C24H29N5OS2 1

84% 5.5 234.7 449 C25H31N5OS2 1

83% 5.7 241.7 450 C24H27N5O2S 1

88% 5.3 450.2 451 C25H29N5O2S 1

96% 5.4 464.2 452 C26H31N5O2S 1

90% 5.6 239.7 453 C27H33N5O2S 1

90% 5.7 246.7 454 C28H35N5O2S 1

91% 5.9 253.7 455 C25H30N6OS 1

84% 4.8 232.2 456 C26H32N6OS 1

89% 4.9 238.8 457 C27H34N6OS 1

86% 5.0 246.1 458 C28H36N6OS 1

93% 5.2 252.9 459 C29H38N6OS 1

93% 5.4 260.1 460 C24H24N6OS 1

68% 5.6 445.2 461 C25H26N6OS 1

55% 5.5 459.2 462 C26H28N6OS 1

55% 5.6 473.3 463 C27H30N6OS 1

48% 5.7 487.3 464 C28N32N6OS 1

44% 5.9 501.2 465 C20H21N5OS2 1

84% 5.3 412.1 466 C21H23N5OS2 1

86% 5.2 426.2 467 C22H25N5OS2 1

90% 5.3 440.2 468 C23H27N5OS2 1

79% 5.5 227.7 469 C24H29N5OS2 1

91% 5.7 234.8 470 C23H25N5O2S 1

92% 5.5 436.2 471 C24H27N5O2S 1

88% 5.4 450.2 472 C25H29N5O2S 1

93% 5.5 464.3 473 C26H31N5O2S 1

92% 5.6 478.3 474 C27H33N5O2S 1

95% 5.8 246.7 475 C24H28N6OS 1

87% 4.9 224.7 476 C25H30N6OS 1

80% 4.8 231.9 477 C26H32N6OS 1

84% 4.9 238.9 478 C27H34N6OS 1

90% 5.0 245.7 479 C28H36N6OS 1

91% 5.2 505.3

Analyses Ex. No. Formula X R1 R2 Purity rt (min) [M + H]+ 480 C30H34N6O3S S

86% 5.4 559.2 481 C31H36N6O3S S

88% 5.5 573.2 482 C32H38N6O3S S

88% 5.5 587.3 483 C33H40N6O3S S

89% 5.7 601.3 484 C34H42N6O3S S

91% 5.8 615.3 485 C35H36N5O3S S

91% 5.6 621.3 486 C31H34N6O4S S

66% 5.6 587.2 487 C32H36N6O4S S

73% 5.6 601.2 488 C33H38N6O4S S

79% 5.7 615.3 489 C34H40N6O4S S

71% 5.9 629.3 490 C35H42N6O4S S

81% 6.0 643.3 491 C36H36N6O4S S

60% 5.8 649.3 492 C30H34N6O3S S

83% 5.4 559.2 493 C31H36N6O3S S

87% 5.5 573.2 494 C32H36N6O3S S

87% 5.5 587.3 495 C33H40N6O3S S

87% 5.7 601.3 496 C34H42N6O3S S

88% 5.8 615.3 497 C35H36N6O3S S

89% 5.6 621.3 498 C31H34N6O4S S

71% 5.6 587.2 499 C32H36N6O4S S

45% 5.6 601.2 500 C33H38N6O4S S

75% 5.7 615.3 501 C34H40N6O4S S

68% 5.9 629.3 502 C35H42N6O4S S

76% 6.0 643.3 503 C36H36N6O4S S

55% 5.8 649.3 504 C30H34N6O4 O

88% 4.9 543.3 505 C31H36N6O4 O

88% 5.0 557.3 506 C32H38N6O4 O

85% 5.0 571.3 507 C33H40N6O4 O

86% 5.2 585.3 508 C31H34N6O5 O

79% 4.9 571.2 509 C32H36N6O5 O

56% 5.0 585.3 510 C33H38N6O5 O

77% 5.1 599.3 511 C34H40N6O5 O

74% 5.2 613.3 512 C30H34N6O4 O

90% 4.9 543.3 513 C31H36N6O4 O

90% 5.0 557.3 514 C32H38N6O4 O

89% 5.0 571.3 515 C33H40N6O4 O

91% 5.2 585.3 516 C31H34N6O5 O

76% 4.9 571.2 517 C32H36N6O5 O

81% 5.0 585.3 518 C33H38N6O5 O

74% 5.1 599.3 519 C34H40N6O5 O

75% 5.2 613.3 520 C25H26N6OS S

93% 6.8 459.2 521 C26H28N6O5 S

93% 6.6 473.2 522 C27H30N6OS S

90% 6.7 487.2 523 C28H32N6OS S

92% 6.8 501.2 524 C29H34N6OS S

92% 6.9 515.2 525 C30H28N6OS S

89% 6.8 521.2 526 C26H26N6O2S S

63% 7.1 487.2 527 C27H28N6O2S S

87% 6.8 501.2 528 C28H30N6O2S S

85% 6.9 515.2 529 C29H32N6O2S S

79% 7.0 529.2 530 C30H34N6O2S S

91% 7.2 543.2 531 C31H28N6O2S S

80% 7.1 549.2 532 C25H26N6OS S

91% 6.8 459.2 533 C26H28N6OS S

89% 6.6 473.2 534 C27H30N6OS S

93% 6.7 487.2 535 C28H32N6OS S

91% 6.8 501.2 536 C29H34N6OS S

91% 6.9 515.2 537 C30H28N6OS S

87% 6.8 521.2 538 C26H26N6O2S S

90% 7.0 487.2 539 C27H28N6O2S S

61% 6.8 501.2 540 C28H30N6O2S S

87% 6.9 515.2 541 C29H32N6O2S S

83% 7.0 529.2 542 C30H34N6O2S S

93% 7.2 543.2 543 C31H28N6O2S S

76% 7.1 549.2 544 C25H26N6O2 O

91% 6.1 443.2 545 C26H28N6O2 O

90% 6.1 457.2 546 C27H30N6O2 O

87% 6.1 471.2 547 C28H32N6O2 O

88% 6.2 485.2 548 C26H26N6O3 O

93% 6.2 471.2 549 C27H28N6O3 O

91% 6.1 485.2 550 C28H30N6O3 O

81% 6.2 499.2 551 C29H32N6O3 O

82% 6.3 513.2 552 C25H26N6O2 O

91% 6.1 443.2 553 C26H28N6O2 O

91% 6.1 457.2 554 C27H30N6O2 O

89% 6.1 471.2 555 C28H32N6O2 O

91% 6.1 485.2 556 C26H26N6O3 O

93% 6.2 471.2 557 C27H28N6O3 O

95% 6.1 485.2 558 C28H30N6O3 O

85% 6.2 499.2 559 C29H32N6O3 O

85% 6.3 513.2 560 C24H24N6OS S

84% 3.6 445.2 561 C26H28N6OS S

92% 3.5 473.3 562 C27H30N6OS S

83% 3.6 487.3 563 C28H32N6OS S

88% 3.7 501.3 564 C29H26N6OS S

59% 3.7 507.2 565 C24H24N6O2 O

87% 3.2 429.2 566 C25H26N6O2 O

92% 3.1 443.3 567 C26H28N6O2 O

97% 3.1 457.3 568 C27H30N6O2 O

90% 3.1 471.3 569 C24H24N6O2 O

91% 3.1 429.2 570 C25H26N6O2 O

97% 3.1 443.3 571 C26H28N6O2 O

95% 3.1 457.3 572 C27H30N6O2 O

95% 3.2 471.3

Ex. No. Formula R1 R2 Purity rt (min) [M + H]+ 573 C29H25N5OS

93% 6.7 492.2 574 C29H24ClN5OS

93% 7.2 526.2 575 C29H23Cl2N5OS

93% 7.6 560.1 576 C30H27N5OS

94% 7.0 506.2 577 C29H24FN5OS

95% 6.9 510.3 578 C30H27N5OS

90% 6.9 506.3 579 C30H26ClN5OS

92% 7.4 540.2 580 C32H31N5O3S

88% 6.4 566.3 581 C31H29N5OS

87% 7.1 520.2 582 C27H23N5O2S

93% 6.2 482.2 583 C27H27N5O2S

38 + 45% 5.6 +5.71 486.3 584 C28H30N6O2S

87% 4.6 515.3 585 C29H32N6O2S

84% 4.5 529.3 586 C29H34N6OS

89% 4.7 515.3 587 C25H25N5O2S

90% 5.18 m 460.3 588 C26H27N5O2S

87% 5.6 474.3 589 C25H22N4OS2

89% 6.7 459.2 590 C25H21ClN4OS2

87% 7.2 493.2 591 C25H20Cl2N4OS2

90% 7.6 527.1 592 C26H24N4OS2

83% 7.0 473.2 593 C25H21FN4OS2

88% 6.9 477.2 594 C26H24N4OS2

80% 7.0 473.2 595 C26H23ClN4OS2

79% 7.4 507.2 596 C28H28N4O3S2

82% 6.4 533.2 597 C27H26N4OS2

79% 7.2 487.2 598 C23H20N4O2S2

80% 6.2 449.2 599 C23H24N4O2S2

31 + 32% 5.7 +5.86 453.2 600 C24H27N5O2S2

80% 4.3 241.7 601 C25H29N5O2S2

81% 4.3 248.8 602 C25H31N5OS2

81% 4.5 482.3 603 C21H22N4O2S2

79% 5.6 427.1 604 C22H24N4O2S2

78% 5.9 441.2 605 C28H26N4O2S

89% 6.8 483.2 606 C28H25ClN4O2S

90% 7.2 517.2 607 C28H24Cl2N4O2S

91% 7.7 551.1 608 C29H28N4O2S

88% 7.0 497.3 609 C28H25FN4O2S

89% 6.9 501.2 610 C29H28N4O2S

87% 7.0 497.3 611 C29H27ClN4O2S

90% 7.5 531.2 612 C31H32N4O4S

91% 6.5 557.2 613 C30H30N4O2S

87% 7.2 511.3 614 C26H24N4O3S

89% 6.3 473.2 615 C26H28N4O3S

39 + 43% 5.7 +5.85 477.2 616 C27H31N5O3S

34% 4.5 506.3 617 C28H33N5O3S

79% 4.4 520.3 618 C28H35N5O2S

76% 4.6 506.3 619 C24H26N4O3S

85% 5.7 451.2 620 C25H28N4O3S

84% 5.9 465.2 621 C29H29N5OS

89% 5.9 248.8 622 C29H28ClN5OS

89% 6.4 265.7 623 C29H27Cl2N5OS

93% 6.9 282.7 624 C30H31N5OS

90% 6.2 255.8 625 C29H28FN5OS

92% 6.1 257.8 626 C30H31N5OS

87% 6.2 255.8 627 C30H30ClN5OS

90% 6.8 272.7 628 C32H35N5O3S

87% 5.6 285.8 629 C31H33N5OS

88% 6.4 262.8 630 C27H27N5O2S

89% 5.4 243.7 631 C27H31N5O2S

31 + 37% 5.26 +5.33 245.6 632 C28H34N6O2S

79% 3.7 260.3 633 C29H36N6O2S

77% 3.7 267.3 634 C29H38N6OS

78% 3.9 260.2 635 C25H29N5O2S

80% 4.9 232.7 636 C26H31N5O2S

79% 5.0 239.7 637 C28H23F3N4O2S

88% 7.4 537.2 638 C28H22ClF3N4O2S

90% 7.8 571.1 639 C28H21Cl2F3N4O2S

92% 8.3 605.1 640 C29H25F3N4O2S

89% 7.6 551.2 641 C28H22F4N4O2S

189% 7.5 555.2 642 C29H25F3N4O2S

88% 7.7 551.2 643 C29H24ClF3N4O2S

90% 8.1 585.1 644 C31H29F3N4O4S

92% 7.2 611.2 645 C30H27F3N4O2S

86% 7.8 565.2 646 C26H21F3N4O3S

88% 7.0 527.2 647 C26H25F3N4O3S

44 + 42% 6.59 +6.7 531.2 648 C27H28F3N5O3S

81% 5.0 280.8 649 C28H30F3N5O3S

82% 5.0 287.8 650 C28H32F3N5O2S

86% 5.2 280.8 651 C24H23F3N4O3S

90% 6.6 505.2 652 C25H25F3N4O3S

88% 6.8 519.2

Ex. No. Formula R1 R2 Purity rt (min) [M + H]+ 653 C29H32N6O3S

88% 6.4 545.3 654 C30H34N6O3S

90% 6.3 559.3 655 C31H36N6O3S

89% 6.3 573.3 656 C32H38N6O3S

91% 6.5 587.3 657 C33H40N6O3S

91% 6.8 601.3 658 C25H29N5O3S2

78% 6.7 512.3 659 C26H31N5O3S2

87% 6.5 526.3 660 C27H33N5O3S2

86% 6.6 540.3 661 C28H35N5O3S2

84% 6.8 554.3 662 C29H37N5O3S2

83% 7.0 568.3 663 C28H33N5O4S

83% 6.7 536.3 664 C29H35N5O4S

88% 6.6 550.3 665 C30H37N5O4S

84% 6.6 564.3 666 C31H39N5O4S

86% 6.8 578.3 667 C32H41N5O4S

86% 7.0 592.3 668 C29H36N6O3S

82% 5.8 549.3 669 C30H38N6O3S

80% 5.7 563.3 670 C31H40N6O3S

84% 5.8 577.3 671 C32H42N6O3S

84% 6.0 591.4 672 C33H44N6O3S

84% 6.3 605.4 673 C28H30F3N5O4S

82% 7.5 590.3 674 C29H32F3N5O4S

81% 7.3 604.3 675 C30H34F3N5O4S

84% 7.4 618.3 676 C31H36F3N5O4S

86% 7.5 632.3 677 C32H38F3N5O4S

88% 7.7 646.3 678 C29H34N6O4S

81% 5.8 563.3 679 C30H36N6O4S

81% 5.8 577.3 680 C31H38N6O4S

82% 5.8 591.3 681 C32H40N6O4S

82% 6.0 605.3 682 C33H42N6O4S

83% 6.2 619.4

Ex. No. Formula R1 R2 Purity rt (min) [M + H]+ 683 C27H30N6O5S

77% 6.9 551.3 684 C28H32N6O5S

75% 6.8 565.3 685 C29H34N6O5S

81% 6.9 579.3 686 C30H36N6O5S

82% 7.0 593.3 687 C31H38N6O5S

82% 7.3 607.3 688 C27H37N5O3S

77% 7.5 512.3 689 C28H39N5O3S

71% 7.3 526.4 690 C29H41N5O3S

76% 7.3 540.3 691 C30H43N5O3S

74% 7.5 554.4 692 C31H45N5O3S

74% 7.7 568.4 693 C24H24N6OS

47% 4.2 445.3 694 C25H26N6OS

45% 3.9 459.3 695 C26H28N6OS

52% 4.0 473.3 696 C27H30N6OS

43% 4.1 487.3 697 C28H32N6OS

38% 4.3 501.3 698 C20H21N5OS2

78% 4.1 412.2 699 C21H23N5OS2

81% 4.0 426.3 700 C22H25N5OS2

84% 4.1 440.2 701 C23H27N5OS2

86% 4.2 454.3 702 C24H29N5OS2

85% 4.3 468.3 703 C23H25N5O2S

82% 4.2 436.3 704 C24H27N5O2S

84% 4.1 450.3 705 C25H29N5O2S

88% 4.2 464.3 706 C26H31N5O2S

88% 4.3 478.3 707 C27H33N5O2S

87% 4.4 492.3 708 C24H28N6OS

80% 3.5 449.3 709 C25H30N6OS

83% 3.4 436.3 710 C26H32N6OS

84% 3.5 477.3 711 C27H34N6OS

84% 3.6 491.3 712 C28H36N6OS

85% 3.8 505.3 713 C23H22F3N5O2S

83% 4.8 490.3 714 C24H24F3N5O2S

84% 4.8 504.2 715 C25H26F3N5O2S

88% 4.8 518.2 716 C26H28F3N5O2S

91% 4.9 532.2 717 C27H30F3N5O2S

90% 5.0 546.2 718 C24H26N6O2S

70% 3.6 463.3 719 C25H28N6O2S

82% 3.5 477.3 720 C26H30N6O2S

83% 3.5 491.3 721 C27H32N6O2S

89% 3.7 505.3 722 C28H34N6O2S

89% 3.8 519.3 723 C22H22N6O3S

81% 4.3 451.2 724 C23H24N6O3S

80% 4.3 465.2 725 C24H26N6O3S

89% 4.3 479.2 726 C25H28N6O3S

86% 4.4 493.3 727 C26H30N6O3S

86% 4.5 507.3 728 C22H29N5OS

79% 4.8 412.3 729 C23H31N5OS

75% 4.6 426.3 730 C24H33N5OS

78% 4.6 440.3 731 C25H35N5OS

78% 4.7 454.3 732 C26H37N5OS

83.8%   5.0 468.2

Ex. No. Formula R1 R2 Purity rt (min) [M + H]+ 733 C28H24N6OS

45% 4.7 493.2 734 C29H26N6OS

57% 4.2 507.3 735 C24H21N5OS2

69% 4.7 460.2 736 C25H23N5OS2

77% 4.2 474.2 737 C27H25N5O2S

73% 4.8 484.3 738 C28H27N5O2S

76% 4.3 497.3 739 C28H28N6OS

67% 3.9 497.3 740 C29H30N6OS

62% 3.6 511.3 741 C27H22F3N5O2S

61% 5.7 538.2 742 C28H24F3N5O2S

75% 4.9 552.2 743 C28H26N6O2S

57% 4.0 511.2 744 C29H28N6O2S

60% 3.7 525.3 745 C26H22N6O3S

70% 5.0 499.2 746 C27H24N6O3S

65% 4.4 513.2 747 C26H29N5OS

78% 5.4 460.3 748 C27H31N5OS

80% 4.7 474.3 749 C34H34N6O3S

86% 6.6 593.3 750 C33H32N6O3S

82% 6.5 607.3 751 C30H31N5O3S2

77% 6.7 560.2 752 C29H29N5O3S2

77% 6.7 574.2 753 C33H35N5O4S

81% 6.8 584.3 754 C32H33NSO4S

76% 6.7 598.3 755 C34H38N6O3S

77% 5.9 597.3 756 C33H36N6O3S

74% 5.8 611.3 757 C33H32F3N5O4S

76% 7.4 638.3 758 C32H30F3N5O4S

74% 7.3 652.3 759 C34H36N6O4S

78% 6.1 611.3 760 C33H34N6O4S

76% 6.0 625.3 761 C32H32N6O5S

74% 6.9 599.2 762 C31H30N6O5S

69% 6.8 613.3 763 C32H39N5O3S

78% 7.3 560.3 764 C31H37N5O3S

74% 7.5 574.3 765 C31H34N6O4S

76% 6.9 587.2 766 C32H36N6O4S

88% 6.8 601.3 767 C33H38N6O4S

81% 6.8 615.3 768 C34H40N6O4S

84% 7.0 629.3 769 C35H42N6O4S

78% 7.2 643.4 770 C36H36N6O4S

83% 6.8 649.3 771 C31H34N6O4S

81% 6.9 587.2 772 C32H36N6O4S

76% 6.8 601.3 773 C33H38N6O4S

82% 6.8 615.3 774 C34H40N6O4S

84% 7.0 629.3 775 C35H42N6O4S

13% 7.2 643.3 776 C36H36N6O4S

71% 6.8 649.3 777 C26H26N6O2S

84% 4.4 487.3 778 C27H28N6O2S

85% 4.4 501.3 779 C28H30N6O2S

65% 4.4 515.3 780 C29H32N6O2S

75% 4.6 529.3 781 C30H34N6O2S

84% 4.7 543.3 782 C31H28N6O2S

82% 4.5 549.3 783 C26H26N6O2S

87% 4.4 487.3 784 C27H28N6O2S

87% 4.4 501.3 785 C28H30N6O2S

83% 4.4 515.3 786 C29H32N6O2S

91% 4.5 529.3 787 C30H34N6O2S

84% 4.7 543.3 788 C31H28N6O2S

79% 4.5 549.3 789 C24H24N6OS

42% 4.3 445.3 790 C25H26N6OS

72% 4.1 459.3 791 C26H28N6OS

87% 4.1 473.4 792 C27H30N6OS

88% 4.3 487.4 793 C28H32N6OS

92% 4.4 501.4 794 C29H26N6OS

78% 4.3 507.3 795 C24H24N6OS

46% 4.3 445.3 796 C25H26N6OS

71% 4.1 459.3 797 C26H28N6OS

93% 4.1 473.4 798 C27H30N6OS

94% 4.3 487.4 799 C28H32N6OS

86% 4.5 501.4 800 C29H26N6OS

77% 507.3

Ex. No. Formula R1 R2 Purity rt (min) [M + H]+ 801 C30H30N4OS

96% 7.7 495.3 802 C30H29ClN4OS

97% 8.1 529.3 803 C30H28Cl2N4OS

99% 8.6 563.2 804 C31H32N4OS

95% 7.9 509.3 805 C30H29FN4OS

96% 7.8 513.3 806 C31H32N4OS

93% 7.9 509.3 807 C31H31ClN4OS

95% 8.4 543.3 808 C33H36N4O3S

93% 7.4 569.3 809 C32H34N4OS

94% 8.1 523.3 810 C28H28N4O2S

96% 7.2 485.3 811 C28H32N4O2S

37 +44% 6.7 + 6.84 489.3 812 C29H35N5O2S

88% 5.3 518.3 813 C30H37N5O2S

94% 5.3 532.4 814 C30H39N5OS

89% 5.4 518.4 815 C26H30N4O2S

92% 6.7 463.3 816 C27H32N4O2S

91% 6.9 477.3 817 C29H27N5O2S

93% 6.0 510.3 818 C29H26ClN5O2S

87% 6.5 544.2 819 C29H25Cl2N5O2S

74% 6.9 578.2 820 C20H29N5O2S

94% 6.2 524.3 821 C29H26FN5O2S

94% 6.2 528.3 822 C30H29N5O2S

93% 6.3 524.3 823 C30H28ClN5O2S

93% 6.7 558.2 824 C32H33N5O4S

91% 5.7 584.3 825 C31H31N5O2S

89% 6.5 538.3 826 C27H25N5O3S

90% 5.5 500.3 827 C27H29N5O3S

27% +24 4.99 + 5.1  504.3 828 C28H32N6O3S

85% 3.9 533.3 829 C29H34N6O3S

87% 3.9 547.3 830 C29H36N6O2S

88% 4.1 533.3 831 C25H27N5O3S

92% 4.9 478.3 832 C26H29N5O3S

93% 5.1 492.3 833 C27H23N5O3S

93% 7.0 498.3 834 C27H22ClN5O3S

85% 7.4 532.2 835 C27H21Cl2N5O3S

88% 7.8 566.1 836 C28H25N5O3S

90% 7.3 512.3 837 C27H22FN5O3S

88% 7.1 516.2 838 C28H25N5O3S

90% 7.3 512.3 839 C28H24ClN5O3S

91% 7.8 546.2 840 C30H29N5O5S

92% 6.8 572.2 841 C29H27N5O3S

94% 7.5 526.3 842 C25H21N5O4S

89% 6.6 488.2 843 C25H25N5O4S

46% +45 6.24 + 6.4  492.3 844 C26H28N6O4S

82% 4.6 521.3 845 C27H30N6O4S

84% 4.6 535.3 846 C27H32N6O3S

76% 4.8 521.3 847 C23H23N5O4S

90% 6.1 466.2 848 C24H25N5O4S

90% 6.3 480.3 849 C24H21N5OS2

87% 6.1 460.2 850 C24H20ClN5OS2

53% 6.6 494.1 851 C24H19Cl2N5OS2

85% 7.0 528.0 852 C25H23N5OS2

79% 6.2 474.1 853 C24H20FN5OS2

76% 6.2 478.1 854 C25H23N5OS2

74% 6.4 474.1 855 C25H22ClN5OS2

82% 6.9 508.1 856 C27H27N5O3S2

73% 5.8 534.1 857 C26H25N5OS2

74% 6.6 488.1 858 C22H19N5O2S2

77% 5.5 450.1 859 C22H23N5O2S2

23 +25% 5.2 + 5.33 454.1 860 C23H26N6O2S2

78% 3.9 483.2 861 C24H28N6O2S2

68% 3.9 497.2 862 C24H30N6OS2

59% 4.1 483.2 863 C20H21N5O2S2

68% 5.0 428.1 864 C21H23N5O2S2

65% 5.3 442.1 865 C27H30N4OS

97% 7.4 459.2 866 C27H29ClN4OS

98% 7.9 493.2 867 C27H28Cl2N4OS

97% 8.4 527.1 868 C28H32N4OS

98% 7.6 473.2 869 C27H29FN4OS

96% 7.6 477.2 870 C28H32N4OS

94% 7.7 473.2 871 C28H31ClN4OS

96% 8.3 507.2 872 C30H36N4O3S

94% 7.2 533.2 873 C29H34N4OS

91% 7.9 487.2 874 C25H28N4O2S

95% 6.9 449.2 875 C25H32N4O2S

38 + 8% 6.9 + 7.04 453.2 876 C26H35N5O2S

94% 5.0 482.2 877 C27H37N5O2S

93% 5.0 496.3 878 C27H39N5OS

94% 5.2 482.3 879 C23H30N4O2S

95% 6.5 427.2 880 C24H32N4O2S

97% 6.7 441.2 881 C29H27ClN4OS

78% 7.7 515.2 882 C29H28N4OS

59% 7.2 481.2 883 C21H32N4OS

63% 8.6 617.2 884 C31H30N4O2S

61% 7.1 523.2 885 C32H34N4OS

60% 7.9 523.3 886 C31H33N5OS

28% 6.7 524.2 887 C29H27N5O3S

53% 7.6 526.2 888 C29H27BrN4OS

68% 7.8 559 1 889 C29H26F2N4OS

62% 7.3 517.2 890 C29H27N7OS

64% 7.6 522.2 891 C30H27N5OS

66% 7.3 506.2 892 C20H28N4O3S

62% 7.1 525.2 893 C29H26ClN5O3S

55% 7.9 560.1 894 C33H36N4OS

59% 8.1 537.3 895 C30H30N4OS

67% 7.9 565.2 896 C31H32N4OS

57% 7.7 509.2 897 C28H24ClN5O2S

64% 6.2 530.1 898 C28H25N5O2S

64% 5.6 496.2 899 C30H29N5O2S

52% 7.1 632.2 900 C30H27N5O3S

57% 5.5 538.2 901 C31H31NSO2S

65% 6.4 538.2 902 C30H30N6O2S

29% 5.0 539.2 903 C28H24N6O4S

51% 6.0 541.2 904 C28H24BrN5O2S

72% 6.3 574.0 905 C28H23F2N5O2S

66% 5.7 532.2 906 C28H24N8O2S

52% 6.1 537.2 907 C29H24N6O2S

65% 5.7 521.1 908 C29H25N5O4S

66% 5.5 540.1 909 C28H23ClN6O4S

55% 6.4 575.1 910 C32H33N5O2S

64% 6.6 552.2 911 C29H27N5O2S

68% 6.5 580.1 912 C30H29N5O2S

68% 6.1 524.2 913 C26H20ClN5O3S

60% 7.0 518.1 914 C26H21N5O3S

63% 6.6 484.2 915 C28H25N5O3S

41% 7.8 620.1 916 C28H23N5O4S

51% 6.4 526.1 917 C29H27N5O3S

64% 7.3 526.2 918 C28H26N6O3S

21% 6.2 527.2 919 C26H20N6O5S

27% 6.8 529.1 920 C26H20BrN5O3S

61% 7.2 562.0 921 C26H19F2N5O3S

55% 6.6 520.1 922 C26H20N8O3S

61% 7.0 525.1 923 C27H20N6O3S

50% 6.6 509.1 924 C27H21N5O5S

68% 6.5 528.1 925 C26H19ClN6O5S

44% 7.2 563.1 926 C30H29N5O3S

60% 7.5 540.2 927 C27H23N5O3S

62% 7.3 568.1 928 C28H25N5O3S

60% 7.0 512.2 929 C23H18ClN5OS2

28% 6.4 480.1 930 C23H19N5OS2

22% 5.8 446.1 931 C25H23N5OS2

34% 7.3 582.1 932 C25H21N5O2S2

25% 5.7 488.1 933 C26H25N5OS2

21% 6.6 488.1 934 C25H24N6OS2

13% 5.3 489.1 935 C23H18N6O3S2

23% 6.2 491.1 936 C23H18BrN5OS2

38% 6.5 524.0 937 C23H17F2N5OS2

58% 5.8 482.1 938 C23H18N8OS2

28% 6.3 487.1 939 C24H18N6OS2

32% 5.9 471.1 940 C24H19N5O3S2

23% 5.7 490.1 941 C23H17ClN6O3S2

33% 6.7 525.0 942 C27H27N5OS2

29% 6.8 502.2 943 C24H21N5OS2

35% 6.7 530.1 944 C25H23N5OS2

16% 6.3 474.1 945 C26H27ClN4OS

61% 7.5 479.2 946 C26H28N4OS

54% 7.0 445.2 947 C28H32N4OS

61% 8.4 581.1 948 C28H30N4O2S

49% 6.9 487.2 949 C29H34N4OS

57% 7.7 487.2 950 C28H33N5OS

16% 6.4 488.2 951 C26H27N5O3S

44% 7.4 490.2 952 C26H27BrN4OS

70% 7.6 523.1 953 C26H26F2N4OS

61% 7.0 481.2 954 C26H27N7OS

66% 7.4 486.2 955 C27H27N5OS

68% 7.1 470.2 956 C27H28N4O3S

63% 6.9 489.2 957 C26H26ClN5O3S

66% 7.7 524.1 958 C30H36N4OS

58% 7.9 501.3 959 C27H30N4OS

64% 7.7 529.2 960 C28H32N4OS

46% 7.5 473.2

No. Formula R1 R2 Purity rt (min) [M + H]+  961 C30H30N4O3

57% 10.5 495.2  962 C30H27F3N4O2

69% 11.6 533.2  963 C29H28N4O2

69% 10.4 465.2  964 C29H27N5O4

61% 11.0 510.2  965 C30H29ClN4O2

74% 11.6 513.2  966 C32H32N4O4

52% 11.0 537.2  967 C29H27BrN4O2

76% 11.2 543.1  968 C29H27FN4O2

60% 10.7 483.2  969 C29H26Cl2N4O2

68% 11.9 533.1  970 C31H30N4O3

71% 10.3 507.2  971 C30H30N4O2S

72% 10.9 511.2  972 C30H27F3N4O3

77% 11.6 549.2  973 C29H27BrN4O2

66% 11.3 543.1  974 C32H34N4O2

85% 11.5 507.3  975 C29H26F2N4O2

72% 10.8 501.2  976 C32N34N4O5

71% 10.3 555.2  977 C29H27N5O4

72% 8.0 510.2  978 C29H24F3N5O3

70% 9.3 548.2  979 C28H25N5O3

79% 7.8 480.2  980 C28H24N6O5

62% 8.6 525.2  981 C29H26ClN5O3

71% 9.1 528.2  982 C31H29N5O5

65% 8.6 552.2  983 C28H24BrN5O3

82% 8.8 558.1  984 C28H24FN5O3

73% 8.2 498.2  985 C28H23Cl2N5O3

66% 9.5 548.1  986 C30H27N5O4

81% 7.7 522.2  987 C29H27N5O3S

79% 8.4 526.2  988 C29H24F3N5O4

83% 9.3 564.2  989 C28H24BrN5O3

69% 8.8 558.1  990 C31H31N5O3

84% 9.2 522.3  991 C28H23F2N5O3

86% 8.1 516.2  992 C31H31N5O6

60% 7.7 570.2  993 C27H23N5O5

76% 9.5 498.2  994 C27H20F3N5O4

71% 10.7 536.1  995 C26H21N5O4

85% 9.4 488.2  996 C26H20N6O6

56% 10.0 513.2  997 C27H22ClN5O4

77% 10.7 516.1  998 C29H25N5O6

64% 10.2 540.2  999 C26H20BrN5O4

83% 10.4 546.0 1000 C26H20FN5O4

74% 9.8 486.2 1001 C26H19Cl2N5O4

69% 11.0 536.1 1002 C28H23N5O5

81% 9.3 510.2 1003 C27H23N5O4S

79% 10.1 514.1 1004 C27H20F3N5O5

74% 10.8 552.1 1005 C26H20BrN5O4

66% 10.4 546.0 1008 C29H27N5O4

84% 10.8 510.2 1007 C26H19F2N5O4

76% 9.8 504.1 1008 C29H27N5O7

74% 9.3 558.2 1009 C24H21N5O3S

60% 8.2 460.1 1010 C24H18F3N5O2S

65% 9.5 498.1 1011 C23H19N5O2S

77% 8.0 430.1 1012 C23H18N6O4S

60% 8.7 475.1 1013 C24H20ClN5O2S

62% 9.4 478.1 1014 C26H23N5O4S

63% 8.9 502.2 1015 C23H18BrN5O2S

79% 9.1 508.0 1016 C23H18FN5O2S

63% 8.4 448.1 1017 C23H17Cl2N5O2S

54% 9.8 498.1 1018 C25H21N5O3S

62% 8.0 472.1 1019 C24H21N5O2S2

73% 8.8 476.1 1020 C24H18F3N5O3S

70% 9.6 514.1 1021 C23H18BrN5O2S

60% 9.2 508.0 1022 C26H25N5O2S

74% 9.6 472.2 1023 C23H17F2N5O2S

62% 8.3 466.1 1024 C26H25N5O5S

64% 8.0 520.1 1025 C27H22F2N4O3

76% 9.4 489.2 1028 C27H19F5N4O2

77% 10.6 527.1 1027 C26H20F2N4O2

87% 9.2 459.2 1028 C26H19F2N5O4

79% 9.9 504.1 1029 C27H21ClF2N4O2

74% 10.6 507.1 1030 C29H24F2N4O4

89% 10.1 531.2 1031 C26H19BrF2N4O2

82% 10.3 537.1 1032 C26H19F3N4O2

79% 9.7 477.1 1033 C26H18Cl2F2N4O2

69% 11.0 527.1 1034 C28H22F2N4O3

82% 9.2 501.2 1035 C27H22F2N4O2S

76% 9.9 505.1 1036 C27H19F5N4O3

83% 10.7 543.1 1037 C26H19BrF2N4O2

68% 10.4 537.1 1038 C29H26F2N4O2

86% 10.7 501.2 1039 C26H18F4N4O2

80% 9.6 495.1 1040 C29H26F2N4O5

43% 9.2 549.2

No. Formula R′3 R4 Purity rt (min) [M + H]+ 1041 C26H33N5OS2

56   3.69 496.3 1042 C29H37N5O2S

74   3.78 520.3 1043 C30H36N6OS

76   3.77 529.3 1044 C31H38N6OS

73   3.85 543.3 1045 C30H39N5OS

63   4.19 518.3 1046 C30H36N6OS

71   4.01 529.3

No. Formula R′3 R4 Purity rt (min) [M + H]+ 1047 C27H35N5OS2

69   3.65 510.3 1048 C30H39N5O2S

75   3.75 534.3 1049 C31H42N6OS

71   3.49 547.3 1050 C31H38N6OS

66   3.74 543.3 1051 C31H38N6OS

87   3.89 543.3

No. Formula R′3 R4 Purity rt (min) [M + H]+ 1052 C30H36N6OS

 83.38 4.71 529.3 1053 C26H33N5OS2

 72.31 4.41 496.3 1054 C29H37N5O2S

 71.47 4.5 520.3 1055 C30H40N6OS

 62.38 3.86 533.3 1056 C25H32N6OS2

25.6 3.9 497.2 1057 C28H33F2N5OS

63.2 4.5 526.3 1058 C31H41N5OS

 69.01 5.17 532.4 1059 C28H34N6O3S

 73.01 4.58 535.3 1060 C28H41N5OS

44.6 4.9 496.4 1061 C29H34F3N5O2S

80.9 5.1 574.2 1062 C30H39N5OS

 58.64 4.91 518.3 1063 C36H42N6OS

 54.23 5.3 607.3 1064 C28H34BrN5OS

 76.51 4.86 568.2 1065 C28H33Cl2N5OS

 74.91 5.03 558.2 1066 C29H34F3N5OS

 66.26 4.93 558.2 1067 C28H34N6O3S

40   4.6 535.2 1068 C32H37N5OS

73.1 4.9 540.3 1069 C29H34N6O5S

55.8 4.58 579.2 1070 C34H39N5OS

64.6 5.2 566.3 1071 C29H34N6OS

 70.75 4.38 515.3 1072 C29H37N5OS

 64.36 4.68 504.3 1073 C35H41N5O2S

40.5 5 596.3 1074 C31H38N6OS

80.4 4 543.3

No. Formula R′3 R4 Purity rt (min) [M + H]+ 1075 C26H32N6O3S2

  45.2% 6.1 541.3 1076 C27H34N6O3S2

  35.3% 6.3 555.3 1077 C28H36N6O3S2

  39.9% 6.5 569.3 1078 C30H38N6O3S2

14.9 +22.82% 6.7 +6.76 595.3 1079 C32H41N5O3S

  70.3% 7.5 576.4 1080 C33H43N5O3S

  71.9% 7.7 590.4 1081 C34H45N5O35

  72.7% 7.9 604.4 1082 C36H47N5O3S

34.6 +34.7% 8.1 +8.28 630.4 1083 C29H33F2N5O3S

  60.6% 6.9 570.3 1084 C30H35F2N5O3S

  62.7% 7.1 584.3 1085 C31H37F2N5O3S

  65.5% 7.3 598.3 1086 C33H39F2N5O3S

33.92% +32.4% 7.5 +4.6 624.3 1087 C29H34BrN5O3S

  65.6% 7.3 612.2 1088 C30H36BrN5O3S

  68.6% 7.5 626.2 1089 C31H38BrN5O3S

  75.2% 7.7 640.3 1090 C33H40BrN5O3S

37.14% +37.1% 7.88 +8.0 666.3 1091 C29H34BrN5O3S

  71.9% 7.3 612.2 1092 C30H36BrN5O3S

  76.2% 7.4 626.2 1093 C31H38BrN5O3S

  77.0% 7.6 640.3 1094 C33H40BrN5O3S

39.4 +39.64% m 7.8 +8.0 666.3 1095 C29H33Cl2N5O3S

  72.1% 7.6 602.2 1096 C30H35Cl2N5O3S

  74.9% 7.7 616.3 1097 C31H37Cl2N5O35

  76.4% 7.9 630.3 1098 C33H39Cl2N5O3S

39.6% +39.16% 8.1 +8.4 656.3 1099 C30H34F3N5O3S

  64.3% 7.3 602.3 1100 C31H36F3N5O3S

  71.3% 7.5 616.3 1101 C32H38F3N5O3S

  71.6% 7.6 630.3 1102 C34H40F3N5O3S

34.8 +34.91% 8.0 +7.8 656.4 1103 C29H34N6O5S

  63.2% 6.9 579.3 1104 C30H36N6O5S

  66.1% 7.1 593.3 1105 C31H38N6O5S

  66.1% 7.3 607.3 1106 C33H40N6O5S

33.7% +24.4% 7.5 +7.6 633.4 1107 C33H37N5O3S

  84.0% 7.2 584.4 1108 C34H39N5O3S

  86.3% 7.4 598.4 1109 C35H41N5O3S

  86.2% 7.6 612.4 1110 C37H43N5O3S

43.1% +43.4% 7.9 +8.12 638.4 1111 C36H41N5O4S

  58.2% 7.3 640.4 1112 C37H43N5O4S

  61.1% 7.5 654.4 1113 C38H45N5O4S

  67.6% 7.7 668.4 1114 C40H47N5O4S

  38.1% +38.5% 7.9 +8.1 694.4 1115 C21H24N6OS2

  74.0% 3.9 441.2 1116 C22H26N6OS2

  80.2% 4.0 455.3 1117 C23H28N6OS2

  47.3% 4.2 469.3 1118 C25H30N6OS2

18.31% +14% 4.2 +4.3 495.3 1119 C27H33N5OS

  76.8% 5.1 476.4 1120 C28H35N5OS

  77.9% 5.3 490.4 1121 C29H37N5OS

  75.6% 5.4 504.4 1122 C31H39N5OS

38.42% +26.7% m 5.5 +5.7 530.4 1123 C24H25F2N5OS

  68.1% 4.5 470.3 1124 C25H27F2N5OS

  66.9% 4.7 484.3 1125 C26H29F2N5OS

  70.0% 4.8 498.3 1126 C28H31F2N5OS

  25.0% 4.9 524.3 1127 C24H26BrN5OS

  72.7% 4.9 512.2 1128 C25H28BrN5OS

  78.5% 5.0 526.2 1129 C26H30BrN5OS

  80.2% 5.1 540.2 1130 C28H32BrN5OS

39.21% +27% 5.3 +5.4 566.2 1131 C24H26BrN5OS

  77.9% 4.9 512.2 1132 C25H28BrN5OS

  81.4% 5.0 526.2 1133 C26H30BrN5OS

78.25%* 5.1 540.2 1134 C26H32BrN5OS

31.02% +27.9 5.2 +5.4 566.2 1135 C24H25Cl2N5OS

  79.9% 5.1 502.2 1136 C25H27Cl2N5OS

  81.2% 5.2 516.2 1137 C26H29Cl2N5OS

  80.1% 5.3 530.2 1138 C28H31Cl2N5OS

33.63% +28.8% 5.4 +5.6 556.2 1139 C25H26F3N5OS

  73.7% 4.9 502.3 1140 C26H28F3N5OS

  80.8% 5.1 516.2 1141 C27H30F3N5OS

76.86%* 5.2 530.3 1142 C29H32F3N5OS

27.7% +27.3 5.3 +5.4 556.3 1143 C24H26N6O3S

  70.7% 4.6 479.3 1144 C25H28N6O3S

  72.3% 4.7 493.3 1145 C26H30N6O3S

  72.4% 4.8 507.3 1146 C28H32N6O3S

27.5% +26.5% 4.9 +5.3 533.3 1147 C28H29N5OS

  88.2% 4.8 484.3 1148 C29H31N5OS

  89.1% 5.0 498.3 1149 C30H33N5OS

  89.9% 5.1 512.3 1150 C32H35N5OS

46.67% +31.0 5.3 +5.5 538.3 1151 C31H33N5O2S

  46.0% 5.0 540.3 1152 C32H35N5O2S

  46.6% 5.1 554.2 1153 C33H37N5O2S

  54.2% 5.2 568.3 1154 C35H39N5O2S

28 +21% 5.3 +5.5 594.3

No. Formula R′3 R4 Purity rt (min) [M + H]+ 1155 C29H34N6O5S

82% 6.5 579.3 1156 C30H36N6O5S

85% 6.7 593.3 1157 C31H38N6O5S

84% 6.9 607.4 1158 C33H40N6O5S

42 +42% 7.1 +7.28 633.4 1159 C30H34N6O7S

78% 6.5 623.3 1160 C30H36N6O7S

82% 6.7 637.3 1161 C32H38N6O7S

80% 6.9 651.3 1162 C34H40N6O7S

34 +41% 7.1 +7.2 677.4 1163 C35H39N5O3S

83% 7.1 610.4 1164 C36H41N5O3S

84% 7.3 624.4 1165 C37H43N5O3S

85% 7.5 638.4 1166 C39H45N5O3S

41 +42% 7.7 +7.9 664.4 1167 C33H37N5O3S

91% 6.9 584.4 1168 C34H39N5O3S

90% 7.1 598.4 1169 C35H41N5O3S

89% 7.3 612.4 1170 C37H43N5O3S

41 +42% 7.5 +7.7 638.4 1171 C30H34N6O3S

85% 6.4 559.3 1172 C31H36N6O3S

87% 6.5 573.3 1173 C32H38N6O3S

81% 6.8 587.4 1174 C34H40N6O3S

42 +43% 6.9 +7.1 613.4 1175 C37H43N5O5S

86% 6.9 670.4 1176 C38H45N5O5S

82% 7.1 684.5 1177 C39H47N5O5S

86% 7.3 698.5 1178 C41H49N5O5S

38.3 +38.4% 7.5 +7.62 724.4 1179 C31H39N5O3S

86% 6.9 562.4 1180 C32H41N5O3S

87% 7.1 576.4 1181 C33H43N5O3S

86% 7.3 590.4 1182 C35H45N5O3S

38 +39% 7.5 +7.64 616.4 1183 C37H42N6O3S

85% 7.2 651.4 1184 C38H44N6O3S

88% 7.3 665.4 1185 C39H46N6O3S

88% 7.5 679.4 1186 C41H48N6O3S

38.4 +38.5% 7.8 +7.98 705.4 1187 C36H39N5O3S

86% 7.2 622.4 1188 C37H41N5O3S

87% 7.4 636.4 1189 C38H43N5O3S

82% 7.6 650.4 1190 C40H45N503S

40.6 +40.9% 7.8 +8.01 676.4 1191 C31H36N6O3S

85.41%* 6.8 } 1192 C32H38N6O3S

89% 6.8 587.4 1193 C33H40N6O3S

90% 7.0 601.4 1194 C35H42N6O3S

43.1 +44.5% 7.3 +7.45 627.4 1195 C24H26N6O3S

87% 4.3 479.3 1196 C25H28N6O3S

92% 4.4 493.3 1197 C26H30N6O3S

92% 4.6 507.3 1198 C28H32N6O3S

35 +33.9% 4.7 +4.8 533.3 1199 C25H26N6O5S

82% 4.3 523.2 1200 C26H28N6O5S

86% 4.5 537.3 1201 C27H30N6O5S

83% 4.6 551.3 1202 C29H32N6O5S

35 +33.9% 4.7 +4.8 577.3 1203 C30H31N5OS

88% 4.9 510.3 1204 C31H33N5OS

90% 5.0 524.3 1205 C32H35N5OS

89% 5.2 538.3 1206 C34H37N5OS

43 +31% 5.3 +5.4 564.3 1207 C28H29N5OS

92% 4.7 484.3 1208 C29H31N5OS

93% 4.8 498.3 1209 C30H33N5OS

92% 4.9 512.3 1210 C32H35N5OS

43 +30.1% 5.1 538.3 1211 C25H26N6OS

87% 4.1 459.3 1212 C26H28N6OS

86% 4.2 473.3 1213 C27H30N6OS

82% 4.4 487.3 1214 C29H32N6OS

40 +36% 4.5 +4.6 513.3 1215 C32H35N5O3S

87% 4.8 570.3 1216 C33H37N5O3S

84% 4.9 584.3 1217 C34H39N5O3S

86% 5.0 598.3 1218 C36H41N5O3S

32% +29% 5.2 +5.3 624.4 1219 C26H31N5OS

90% 4.6 462.3 1220 C27H33N5OS

92% 4.7 476.4 1221 C28H35N5OS

91% 4.9 490.4 1222 C30H37N5OS

42 +29.9% 5.0 +5.2 516.3 1223 C32H34N6OS

80% 5.0 551.3 1224 C33H36N6OS

90% 5.1 565.3 1225 C34H38N6OS

85% 5.3 579.4 1226 C36H40N6OS

37% +27 5.45.6 605.4 1227 C31H31N5OS

90% 5.0 522.3 1228 C32H33N5OS

91% 5.1 536.3 1229 C33H35N5OS

90% 5.2 550.3 1230 C35H37N5OS

42% +30.8 5.4 +5.5 576.3 1231 C26H28N6OS

68% 4.4 473.4 1232 C27H30N6OS

56% 4.5 487.4 1233 C28H32N6OS

40% 4.7 613.2 1234 C30H34N6OS

40% 4.8 527.4 Pharmacological Properties of the Compounds of the Invention

The compounds of the present invention can and have been tested as regards their affinity for different sub-types of somatostatin receptors according to the procedures described below.

Study of the affinity for the sub-types of human somatostatin receptors:

The affinity of a compound of the invention for sub-types of somatostatin receptors 1 to 5 (sst₁, sst₂, sst₃, sst₄ and sst₅, respectively) is determined by measurement of the inhibition of the bond of [¹²⁵I-Tyr¹¹]SRIF-14 to transfected CHO-K1 cells.

The gene of the sst₁, receptor of human somatostatin has been cloned in the form of a genomic fragment. A segment PstI-XmnI of 1.5 Kb containing 100 bp of the non transcribed 5′ region, 1.17 Kb of the coding region in totality, and 230 bp of the non transcribed 3′ region is modified by the addition of the linker Bg1II. The resulting DNA fragment is subcloned in the BamHI site of a pCMV-81 in order to produce the expression plasmid in mammals (provided by Dr. Graeme Bell, Univ. Chicago). A cloned cell line expressing in a stable fashion the sst₁ receptor is obtained by transfection in CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

The gene of the sst₂ receptor of human somatostatin, isolated in the form of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subcloned in a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ. of Chicago). The expression vector of the mammalian cells is constructed by inserting the BamHl-HindlI fragment of 1.7 Kb in endonuclease restriction sites compatible with the plasmid pCMV5. A cloned cell line is obtained by transfection in CHO-K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as selection marker.

The sst₃ receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a BamHI/HindIII fragment of 2.4 Kb. The expression plasmid in marnmals, pCMV-h3, is constructed by insertion of the NcoI-HindIII fragment of 2.0 Kb in the EcoR1 site of the vector pCMV after modification of the terminations and addition of EcoR1 linkers. A cloned cell line expressing in a stable fashion the sst₃ receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

The expression plasmid of the human sst₄ receptor, pCMV-HX, was provided by Dr. Graeme Bell (Univ. Chicago). This vector contains the genomic fragment coding for the human sst₄ receptor of 1.4 Kb NheI-NheI, 456 pb of the non transcribed 5′ region, and 200 pb of the non transcribed 3′ region, cloned in the XbaI/EcoR1 sites of PCMV-HX. A cloned cell line expressing in a stable fashion the sst₄ receptor is obtained by transfection in CHO-K1 cells (ATCC). by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. The cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

The gene corresponding to the human sst₅ receptor, obtained by the PCR method using a genomic clone as probe, was provided by Dr. Graeme Bell (Univ. Chicago). The resulting PCR fragment of 1.2 Kb contains 21 base pairs of the non transcribed 5′ region, the coding region in totality, and 55 pb of the non transcribed 3′ region. The clone is inserted in an EcoR1 site of the plasmid pBSSK(+). The insert is recovered in the form of a HindIII-XbaI fragment of 1.2 Kb for subcloning in an expression vector in mammals, pCVM5. A cloned cell line expressing in a stable fashion the sst₅ receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. The cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

The CHO-K1 cells which express in a stable fashion the human sst receptors are cultured in an RPMI 1640 medium containing 10% of foetal calf serum and 0.4 mg/ml of geneticin. The cells are collected with 0.5 mM EDTA and centrifuged at 500 g for approximately 5 minutes at approximately 4° C. The pellet is resuspended in Tris 50 mM at pH 7.4 and centrifuged twice at 500 g for approximately 5 minutes at approximately 4° C. The cells are lysed by sonication and centrifuged at 39000 g for approximately 10 minutes at 4° C. The pellet is resuspended in the same buffer and centrifuged at 50000 g for approximately 10 minutes at approximately 4° C. and the membranes in the pellet obtained are stored at −80° C.

The competitive inhibition tests of the bond with [¹²⁵I-Tyr¹¹]SRIF-14 are carried out in duplicate using 96-well polypropylene plates. The cell membranes (10 μg protein/well) are incubated with [¹²⁵I-Tyr¹¹]SRIF-14 (0.05 nM) for approximately 60 min. at approximately 37° C. in a 50 mM HEPES buffer (pH 7.4) containing BSA 0.2%, MgCl₂ 5 mM, Trasylol 200 KIU/ml, bacitricin 0.02 mg/ml, phenylmethylsulphonyl fluoride 0.02 mg/ml.

The bound [¹²⁵I-Tyr ]SRIF-14 is separated from the free [¹²⁵I-Tyr ¹¹]SRIF-14 by immediate filtration through GFIC glass fibre filter plates (Unifilter, Packard) pre-impregnated with 0.1% of polyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filters are washed with 50 mM HEPES buffer at approximately 0-4° C. for approximately 4 seconds and their radioactivity is determined using a counter (Packard Top Count).

The specific bond is obtained by subtracting the non-specific bond (determined in the presence of 0.1 μM of SRIF-14) from the total bond. The data relative to the bond are analyzed by computer-aided.non-linear regression analysis (MDL) and the values of the inhibition constants (Ki) are determined.

Determination of the agonist or antagonist character of a compound of the present invention is carried out using the test described below.

Functional Test: Inhibition of Production of Intracellular cAMP:

CHO-K1 cells expressing the sub-types of human somatostatin receptors (SRIF-14) are cultured in 24-well plates in an RPMI 1640 medium with 10% of foetal calf serum and 0.4 mg/ml of geneticin. The medium is changed the day preceding the experiment.

The cells at a rate of 10⁵ cells/well are washed twice with 0.5 ml of new RPMI medium comprising 0.2% BSA completed. by 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 min at approximately 37 ° C.

The production of cyclic AMP is stimulated by the addition of 1 mM of forskolin (FSK) for 15-30 minutes at approximately 37 ° C.

The inhibitor effect of the somatostatin of an agonist compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10⁻¹² to 10⁻⁶ M) and of the compound to be tested (10⁻¹⁰ M to 10⁻⁵ M).

The antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and of the compound to be tested (10¹⁰ ⁻¹⁰ M to 10⁻⁵ M).

The reaction medium is eliminated and 200 ml of 0.1 N HCl are added. The quantity of cAMP is measured by a radioimmunological test (FlashPlate SMP001A kit, New England Nuclear).

Results:

The tests carried out according to the protocols described above have demonstrated that the compounds of general formula (I) defined in the present Application have a good affinity for at least one of the sub-types of somatostatin receptors, the inhibition constant K_(i) being lower than micromolar for certain exemplified compounds, and in particular for the compounds shown in the Tables I and II below.

TABLE I

R′3 R′4 K_(i)

(CH₂)₃NH₂(CH₂)₄NH₂(CH₂)₅NH₂(CH₂)₆NH₂ <1 μM<1 μM<1 μM<1 μM

(CH₂)₃NH₂(CH₂)₄NH₂(CH₂)₅NH₂(CH₂)₆NH₂ <1 μM<1 μM<1 μM<1 μM

TABLE II

R′3 R′4 K_(i)

(CH₂)₄NH₂(CH₂)₅NH₂(CH₂)₆NH₂(CH₂)₆NMe₂ <1 μM<1 μM<1 μM

(CH₂)₅NH₂(CH₂)₆NH₂(CH₂)₆NMe₂ <1 μM<1 μM<1 μM

(CH₂)₅NH₂(CH₂)₆NH₂(CH₂)₆NMe₂ <1 μM<1 μM<1 μM

(CH₂)₅NH₂(CH₂)₆NH₂(CH₂)₆NMe₂ <1 μM<1 μM<1 μM

(CH₂)₅NH₂(CH₂)₆NH₂(CH₂)₆NMe₂ <1 μM<1 μM<1 μM

(CH₂)₆NMe₂ <1 μM 

1. A method of treating a disorder selected from the group consisting of acromegaly, hypophyseal adenomas, endocrine gastroenteropancreatic tumors bleeding in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula

in racemic or enantiomeric form, R1 is selected from the group consisting of (C₁-C₁₂) alkyl, (C₀-C₆)alkyl-C(O)—O-Z1, (C₀-C₆)alkyl-C(O)—NH—(CH₂)_(p)-Z₂ and unsubstituted or substituted aryl, Z1 is selected from the group consisting of H, (C₁-C₆)alkyl and —(CH₂)_(p)-aryl; Z2 is selected from the group consisting of amino, (C₁-C₁₂)alkylamino, (C₃-C₈)cycloalkylamino, N,N-di-(C₁-C₁₂) alkylamino, NH—C—(O)—O—(CH₂)_(p)-phenyl, NH—C(O)—O—(CH₂)_(p)—(C₁-C₆)alkyl, phenyl, naphthyl, pyridinyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofuranyl, benzothiophenyl and phthalimidyl, carbocyclic aralkyl selected from the group consisting of benzyl, phenylpropyl and phenylbutyl and heterocyclic aralkyl selected from the group consisting of indolylalkyl and phthalimidoalkyl and unsubstituted or substituted heterocyclic non-aromatic; R2 is selected from the group consisting of H, (C₁-C₁₂) alkyl and aryl optionally substituted; R3 is H or(CH₂)_(p)-Z3; Z3 is selected from the group consisting of (C₁-C₁₂)alkyl, (C₁-C₁₂)alkenyl, (C₃-C₈) cycloalkyl, Y1-(CH₂)_(p)-phenyl-(X1)_(n), —S—(C₁-C₁₂)alkyl, S—(C₁-C₁₂)alkyl-S—S—(C₁-C₁₂) alkyl, and unsubstituted or substituted carbocyclic or heterocyclic aryl;

bis-arylalkyl or

Y1 is O, S, NH or is absent; R4 is (CH₂)_(p)-Z4; Z4 is selected from the group consisting of amino, (C₁-C₁₂)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₁₂)alkylamino, N,N-di-(C₁-C₁₂)alkylamino, amino (C₃-C₆) cycloalkyl, amino (C₁-C₆) alkyl (C₃-C₈) cycloalkyl (C₁-C₆) alkyl, carbocyclic or heterocyclic aminoaryl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkenyl, N—C(O)O(C₁-C₆) alkyl, unsubstituted or substituted carbocyclic or heterocyclic aryl, unsubstituted or substituted heterocyclic non-aromatic radical, bis-arylalkyl, di-arylalkyl,

and N (R6)(R7), R6 and R7 taken togetber with the nitrogen atom which they carry form together a heterocycle of 5 to 7 ring members; R5 is selected from the group consisting of H, —(CH₂)_(p)—C(O)—(CH₂)_(p)-Z5, —(CH₂)_(p)-Z5, —(CH₂)_(p)—OZ5 or —(C₀-C₆)alkyl-C(O)—NH—(CH₂)_(p)-Z5, Z5 is unsubstituted or substituted member selected from the group consisting of —(C₁-C₁₂) alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,

it being understood that the above substitutes of Z5 are selected from the group consisting of Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃, —OCF₃, (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy, —(CH₂)_(p)-phenyl-(X₁)_(q), —NH—CO—(C₁-C₆) alkyl, —NH—C(O)O—(C₁-C₆) alkyl, —S—(C₁-C₆) alkyl, —S-phenyl-(X1)_(q), —O—(CH₂)_(p)-phenyl-(X1)_(q), —(CH₂)_(p)—C(O)—O—(C₁-C₆) alkyl, —(CH₂)_(p)—C(O)—(C₁-C₆) alkyl, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)—NH—(C₁-C₆) alkyl, —O—(CH₂)_(p)—N-di((C₁-C₆) alkyl) and (C₀-C₁₂) alkyl-(X1)_(q); X1, each time that it occurs, is independently selected from the group consisting of H, Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃, —OCF₃, (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy, —S—(C₁-C₆) alkyl, —(CH₂)_(p)-amino, —(CH₂)_(p)—NH—(C₁-C₆) alkyl, —(CH₂)_(p)—N-di-((C₁-C₆) alkyl, —(CH₂)_(p)-phenyl and —(CH₂)_(p)—NH—(C₃-C₆)-cycloalkyl; p each time that it occurs is independently an integer from 0 to 6; q each time that it occurs is independently an integer from 1 to 5; X is O or S; n in the chemical structure is 0; n in Z3 is 0; and m is 1, 2 or 3; or a pharmaceutically acceptable salt of said compound sufficient to treat said disorder.
 2. The method of claim 1, wherein R1 is unsubstituted or substituted aryl; R2 is H or alkyl; R3 is selected from the group consisting of

R4 is selected from the group consisting of

R5 is H or alkyl; or a pharmaceutically acceptable salt of said compound.
 3. The method of claim 1, wherein R1 is unsubstituted phenyl or phenyl substituted with a member of the group consisting of halogen, (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy and nitro; R2 and R5 are H or alkyl; R3 is H or (CH₂)_(p)-Z3; Z3 is selected from the group consisting of (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, Y1-(CH₂)_(p)-phenyl-(X1)_(n), unsubstituted or substituted carbocyclic or heterocyclic aryl, unsubstituted or substituted non-aromatic heterocyclic, bis-arylalkyl, di-arylalkyl,

Y1 represents O, S, NH or is absent; R4 is (CH₂)_(p)-Z4; Z4 is selected from the group consisting of amino, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₁-C₁₂) alkylamino, N,N-di-(C₁-C₁₂) alkylamino, amino (C₃-C₆) cycloalkyl, amino (C₁-C₆) alkyl (C₃-C₈) cycloalkyl (C₁-C₆) alkyl, carbocyclic or heterocyclic aminoaryl , an unsubstituted or substituted carbocyclic and heterocyclic aryl, unsubstituted or substituted non-aromatic heterocyclic, bis-arylalkyl, di-arylalkyl,

it being understood that the substituent of substituted phenyl is at least one member of the group consisting of Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃, —OCF₃, (C₁-C₁₂) alkoxy, —(CH₂)_(p)-phenyl-(X1)_(q), —NH—CO—(C₁-C₆) alkyl, —NH—C(O)—(C₁-C₆) alkyl, —S—(C₁C₆) alkyl, —S-phenyl-(X1)_(q), —O—(CH₂)_(p)-phenyl-(X1)_(q), —(CH₂)_(p)—C(O)—O—(C₁-C₆) alkyl, —(CH₂)_(p)—C(O)—(C₁-C₆) alkyl, —O—(CH₂)_(p)—NH₂, —O(CH₂)_(p)—NH —(C₁-C₆)alkyl, —O—(CH₂)_(p)—N-di-((C₁-₆) alkyl and (C₀-C₁₂) alkyl-(X1)_(q); X1, each time that it occurs, is selected from the group consisting of H, Cl, F, Br, I, CF₃, NO₂, OH, NH₂, CN, N₃, —OCF₃, (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy, —S—(C₁-C₆) alkyl, —(CH₂)_(p)-amino, —(CH₂)_(p)—NH—(C₁-C₆) alkyl, —(CH₂)_(p)—N-di-((C₁-C₆) alkyl), —(CH₂)_(p)-phenyl and —(CH₂)_(p)—NH—(C₃-C₆) cycloalkyl; p each time that it occurs is independently an integer from 0 to 6; and q each lime that it occurs is independently an integer from 1 to
 5. 4. The method of claim 3, wherein R1 is phenyl or phenyl substituted by a member selected from the group consisting of halogen, (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy and nitro; R2 and R5 are H or alkyl; R3 is (C₂)_(p)-Z3, Z3 is selected from the group Z3 is selected from the group consisting of (C₃-C₈) cycloalkyl, unsubstituted or substituted phenyl, naphthyl, furanyl, thiophene, indolyl, pyrrolyl and benzothiophene; R4 is (CH₂)_(p)-Z4; Z4 is selected from the group consisting of amino, (C₁-C₁₂) alkylamino, N,N-di-(C₁-C₁₂) alkylamino and amino (C₁-C₆) alkyl (C₃-C₆) cycloalkyl-(C₁-C₆) alkyl; X is S; p each time that it occurs is independently an integer from 0 to 6; n is 0; and m is 1, 2 or
 3. 5. The method of claim 4 selected from the compounds of formulae

wherein R′3 is selected from

and R′3 is selected from

or a pharmaceutically acceptable salt or said compound. 